KR20140053013A - Tricyclic sulfonamide compounds and methods of making and using same - Google Patents

Tricyclic sulfonamide compounds and methods of making and using same Download PDF

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KR20140053013A
KR20140053013A KR1020137032334A KR20137032334A KR20140053013A KR 20140053013 A KR20140053013 A KR 20140053013A KR 1020137032334 A KR1020137032334 A KR 1020137032334A KR 20137032334 A KR20137032334 A KR 20137032334A KR 20140053013 A KR20140053013 A KR 20140053013A
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alkyl
amp
alkoxy
selected
group consisting
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수잔 메리 크램프
헤이즐 조앤 다이크
토마스 데이비드 팔린
로버트 잘러
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자프겐 인크.
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Priority to US61/483,265 priority
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Priority to PCT/US2012/036792 priority patent/WO2012154678A1/en
Publication of KR20140053013A publication Critical patent/KR20140053013A/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/535Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/53751,4-Oxazines, e.g. morpholine
    • A61K31/53831,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/40Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/41641,3-Diazoles
    • A61K31/41881,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/4738Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0053Mouth and digestive tract, i.e. intraoral and peroral administration
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D498/00Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04Ortho-condensed systems

Abstract

The present invention provides their use in the treatment of medical disorders such as tricyclic sulfonamide compounds and obesity. A pharmaceutical composition and a method for preparing various tricyclic compounds are provided. It is also assumed that the compound has an activity against methionyl amino-peptidase 2.

Description

TECHNICAL FIELD The present invention relates to a tricyclic sulfonamide compound, a tricyclic sulfonamide compound, a method for preparing the same, and a method of using the tricyclic sulfonamide compound.

Related application

This application claims priority to U.S. Provisional Patent Application Serial No. 61 / 483,265 filed on May 6, 2011, the basic application of which is hereby incorporated by reference in its entirety.

Over 1.1 billion people worldwide are reported to be overweight. Obesity is estimated to be more than 90 million people in the United States alone. It is believed that 25% of the US population over the age of 20 is clinically obese. Overweight or obesity, while exhibiting problems (e.g., limitation of mobility, discomfort in tight spaces such as theater or airplane seats, social difficulties, etc.), these conditions, particularly clinical obesity, , ≪ / RTI > overweight, or obesity, thereby exacerbating or promoting disease and other adverse health conditions. In the United States, it is estimated that over 300,000 people die annually due to obesity-related conditions (O'Brien et al., Amer J Surgery (2002) 184: 4S-8S; and Hill et al. 280: 1371).

There is no cure for overweight or obesity. For example, conventional medication for treating overweight or obese patients, such as serotonin and noradrenaline reuptake inhibitors, noradrenaline reuptake inhibitors, selective serotonin reuptake inhibitors, intestinal lipase inhibitors, or surgical therapies, such as gastrectomy Or gastrointestinal banding appears to provide minimal short term benefits or significant recurrence rates, with additional adverse side effects to patients being shown.

MetAP2 encodes a protein that functions at least in part by enzymatically removing the amino-terminal methionine residue from certain newly-decoded proteins, such as glyceraldehyde-3-phosphate dehydrogenase (Warder et al . ) J Proteome Res 7 : 4807). Increased expression of the MetAP2 gene has historically been associated with various forms of cancer. Molecules that inhibit the enzymatic activity of MetAP2 have been identified in various tumor types (Wang et al. (2003) Cancer Res 63: 7861) and in infectious diseases such as microporosidosis, leishmaniasis and malaria (Zhang et al. Biomed Sci 9: 34). ≪ / RTI > In particular, the inhibition of MetAP2 activity in obese and obese-diabetic animals reduces body weight by, in part, increasing the oxidation of fat and, in part, by reducing food consumption (Rupnick et al. (2002) Proc. Natl Acad Sci USA 99: 10730).

Such MetAP2 inhibitors can be used to treat conditions associated with excessive hyperlipidemia and hyperplasia, including type 2 diabetes, fatty liver and cardiovascular disease (e. G., By reducing insulin resistance, by reducing liver lipid content and by reducing cardiac load) It can also be useful for patients. Thus, compounds capable of modulating MetAP2 are needed to address the treatment of obesity and related diseases as well as other diseases that respond favorably to MetAP2 modulator therapy.

In this specification, for example, compounds which may be modulators of MetAP2 and their use as medicaments, methods for preparing these compounds, and pharmaceutical compositions containing these compounds, either alone or in combination with other agents, Compositions, and uses of these compounds in the manufacture of a medicament for use in inhibiting MetAP2 activity in warm-blooded animals such as humans. In particular, the invention relates to compounds useful for the treatment of obesity, type 2 diabetes and / or other obesity-related conditions. Also provided is a pharmaceutical composition comprising at least one of the disclosed compounds and a pharmaceutically acceptable carrier.

In one embodiment, provided herein are compounds represented by formula (I): embedded image or a pharmaceutically acceptable salt, stereoisomer, ester or prodrug thereof.

Figure pct00001

Wherein A, B, D, R A1 , R A2 , Y, X and n are as defined herein.

The features and other details of the disclosure will be more particularly described below. Before further description of the invention, certain terms used in the specification, examples, and appended claims are collected here. These definitions should be read in light of the remainder of this specification and should be understood by those of ordinary skill in the art (hereinafter abbreviated as "those skilled in the art "). Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

Justice

"Treating" includes any effects, such as relief, reduction, modulation, or elimination, leading to improvements in conditions, diseases,

The term "alkenyl " as used herein refers to an unsaturated straight or branched chain hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include, for example, straight-chain or branched-chain groups of 2 to 6 or 3 to 4 carbon atoms, referred to herein as C 2-6 alkenyl and C 3-4 alkenyl, respectively, But are not limited thereto. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, and the like.

The term "alkoxy" as used herein refers to a straight or branched alkyl group (alkyl-O-) attached to an oxygen. Exemplary alkoxy groups include, but are not limited to, groups having an alkyl group of one to six or two to six carbon atoms, referred to herein as C 1-6 alkoxy and C 2 -C 6 alkoxy, respectively . Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.

The term "alkoxyalkyl ", as used herein, refers to a straight or branched chain alkyl group attached to an oxygen attached to a second straight or branched chain alkyl group (alkyl-O-alkyl-). Exemplary alkoxyalkyl groups include, but are not limited to, alkoxyalkyl groups having each of the alkyl groups independently comprised of one to six carbon atoms, referred to herein as C 1-6 alkoxy-C 1-6 alkyl It is not. Exemplary alkoxyalkyl groups include, but are not limited to, methoxymethyl, 2-methoxyethyl, 1-methoxyethyl, 2-methoxypropyl, ethoxymethyl, 2-isopropoxyethyl and the like.

The term "alkoxycarbonyl " as used herein refers to a straight or branched chain alkyl group attached to an oxygen (alkyl-OC (O) -) attached to a carbonyl group. Exemplary alkoxycarbonyl groups include, but are not limited to, alkoxycarbonyl groups of one to six carbon atoms, referred to herein as C 1-6 alkoxycarbonyl. Exemplary alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, and the like.

The term "alkenyloxy ", as used herein, refers to a straight or branched chain alkenyl group (alkenyl-O) attached to an oxygen. Exemplary alkenyloxy groups include, but are not limited to, groups having an alkenyl group of 3 to 6 carbon atoms, referred to herein as C 3-6 alkenyloxy. Exemplary "alkenyloxy" groups include, but are not limited to, allyloxy, butenyloxy, and the like.

The term "alkynyloxy " as used herein refers to a straight chain or branched alkynyl group (alkynyl-O) attached to an oxygen. Exemplary alkynyloxy groups include, but are not limited to, groups having an alkynyl group of 3 to 6 carbon atoms, referred to herein as C 3-6 alkynyloxy. Exemplary alkynyloxy groups include, but are not limited to, propynyloxy, butynyloxy, and the like.

The term "alkyl ", as used herein, refers to saturated straight or branched chain hydrocarbons. Exemplary alkyl groups are straight chain or branched alkyl groups of 1 to 6, 1 to 4, or 1 to 3 carbon atoms, each of which is referred to herein as C 1-6 alkyl, C 1-4 alkyl and C 1-3 alkyl. But are not limited to, cyclic groups. Exemplary alkyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, 2-methyl-1-butyl, Methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, Butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, and the like.

The term "alkylcarbonyl" as used herein refers to a straight or branched chain alkyl group (alkyl-C (O) -) attached to a carbonyl group. Exemplary alkylcarbonyl groups include, but are not limited to, an alkylcarbonyl group of one to six atoms, referred to herein as a C 1-6 alkylcarbonyl group. Exemplary alkylcarbonyl groups include, but are not limited to, acetyl, propanoyl, isopropanoyl, butanoyl, and the like.

The term "alkynyl " as used herein refers to an unsaturated straight or branched chain hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include, but are not limited to, straight chain or branched chain groups of 2 to 6 or 3 to 6 carbon atoms, referred to herein as C 2-6 alkynyl and C 3-6 alkynyl, respectively. It is not. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, and the like.

The term "carbonyl ", as used herein, refers to the radical -C (O) -.

The term "cyano, " as used herein, refers to a radical -CN.

The term "cycloalkoxy" as used herein refers to a cycloalkyl group (cycloalkyl-O-) attached to an oxygen. Exemplary cycloalkoxy groups include, but are not limited to, cycloalkoxy groups of 3 to 6 carbon atoms, each referred to herein as a C 3-6 cycloalkoxy group. Exemplary cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclohexyloxy, and the like.

The term "cycloalkyl", or "carbocyclic" as used herein, e.g., in the present specification, each of C 3-6 cycloalkyl or C 4-6 cycloalkyl, referred to as an example, 3 to 6, or Refers to a monocyclic saturated or partially unsaturated hydrocarbon group of 4 to 6 carbons. Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl, or cyclopropyl.

The term "halo" or "halogen ", as used herein, refers to F, Cl, Br or I.

The term "heteroaryl" or "heteroaromatic group ", as used herein, refers to a monocyclic group containing one or more heteroatoms such as nitrogen, oxygen and sulfur, Aromatic 5- to 6-membered ring system. Where possible, the heteroaryl ring may be connected to adjacent radicals via carbon or nitrogen. Exemplary heteroaryl rings include, but are not limited to, furan, thiophene, pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridine and pyrimidine no.

The term "heterocyclyl" or "heterocyclic group" is art-recognized and refers to a saturated or partially unsaturated 4- to 6-membered ring structure in which the ring structure contains 1 to 3 heteroatoms such as nitrogen, 7-membered ring structure. Where possible, the heterocycle may be connected to adjacent radicals via carbon or nitrogen. Examples of heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran or dihydrofuran.

As used herein, "heterocyclyloxy" refers to a heterocyclyl group attached to oxygen (heterocyclyl-O-).

The term "heteroaryloxy ", as used herein, refers to a heteroaryl group (heteroaryl-O-) attached to an oxygen.

The terms "hydroxy" and "hydroxyl ", as used herein, refer to a radical-OH.

The term "oxo ", as used herein, refers to a radical = O.

The term "pharmaceutically or pharmacologically acceptable " includes molecular components and compositions that do not cause adverse reactions, allergic reactions or other side effects when administered to an animal or human as needed. For administration to humans, the formulation must meet the sterility, pyrogenicity, general safety and purity standards required by the FDA Office of Biological Standards.

The term " pharmaceutically acceptable carrier "or" pharmaceutically acceptable excipient "as used herein refers to any and all solvents, dispersion media, coatings, isotonicity and absorption delaying agents Quot; The use of such media and preparations for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds that provide supplemental, additional or improved therapeutic functionality.

The term "pharmaceutical composition" as used herein refers to a composition comprising at least one compound as disclosed herein that is formulated with one or more pharmaceutically acceptable carriers.

"Person", "patient" or "subject" are used interchangeably and refer to a mammal, preferably a mouse, rat, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, Preferably an animal, including humans. The compounds of the present invention may be administered to mammals such as humans, but may be administered to animals in need of veterinary treatment, such as animals (e.g., dogs, cats, etc.), farm animals , Horses, etc.) and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Mammals treated by the methods of the present invention are preferably mammals that are desired to treat obesity or lose weight. "Modulating" includes antagonism (e.g., inhibition), efficacy, partial antagonism and / or partial efficacy.

In the context of the present invention, the term "therapeutically effective amount" refers to the amount of a subject compound that will elicit the biological or medical response of a tissue, line, animal or human being sought by a researcher, veterinarian, do. The compounds of the present invention are administered in therapeutically effective amounts to treat diseases. Alternatively, a therapeutically effective amount of the compound is the amount required to achieve the desired therapeutic and / or prophylactic effect, such as an amount that causes weight loss.

The term " pharmaceutically acceptable salt (s) ", as used herein, refers to salts of acidic or basic groups that may be present in the compounds used in the composition. The compounds contained in the compositions of the present invention which are basic in nature can form a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds include, for example, maleates, oxalates, chlorides, bromides, iodides, nitrates, sulfates, bisulfates, phosphates, acid phosphates, But are not limited to, isonicotinate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, gluconate, gluconic Caro carbonate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethane sulfonate, benzene sulfonate, p-toluenesulfonate and pamoate (i.e., 1,1'-methylene-bis- (2-hydroxy-3-naphthoate) salts), but are not limited to, pharmacologically acceptable As salts containing anions, non-toxic ones of forming acid addition salts. Compounds included in the compositions of the present invention that are inherently acidic can form base salts with a variety of pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, especially calcium, magnesium, sodium, lithium, zinc, potassium and iron salts. Compounds included in the compositions of the present invention, including basic or acidic moieties, may form pharmaceutically acceptable salts with various amino acids. The compounds of the present invention include acidic and basic groups; For example, it may contain both one amino group and one carboxylic acid group. In such cases, the compound may be present as an acid addition salt, a positive ion or a base salt.

The compounds of the present invention may comprise one or more chiral centers and / or double bonds and therefore exist as stereoisomers. As used herein, the term "stereoisomer" is intended to include all enantiomers or diastereomers. These compounds may be denoted by the symbols "(+) "," (-) ", "R ", or" S ", depending on the stereogenic form of the substituents around the stereogenic carbon atom. The present invention includes various stereoisomers of these compounds and mixtures thereof. Enantiomers or mixtures of diastereoisomers are denoted by "(±)" in the nomenclature, but those skilled in the art will recognize that the structure implicitly implies a chiral center.

The compounds of the present invention may contain one or more double bonds and thus exist as geometric isomers resulting from the arrangement of substituents around the carbon-carbon double bond. The symbol designates one bond, which may be a single, double or triple bond as described herein. Substituents around the carbon-carbon double bond are denoted as " Z " or " E " stereoisomers, and the terms " Z " and " E " Unless otherwise indicated, structures representing a double bond include both " E " and " Z " isomers. Substituents around the carbon-carbon double bond may alternatively be referred to as "cis" or "trans", where "cis" represents a substituent on the same side of a double bond and "trans"Lt; / RTI >

The compounds of the present invention may include carbocyclic or heterocyclic rings and therefore exist as geometric isomers resulting from the arrangement of substituents around the ring. Arrangement of the carbon ring or heterocyclic ring substituents of the circumference is marked as the "Z" or "E" three-dimensional shape, the term "Z" and "E" is used in accordance with IUPAC standards. Unless otherwise indicated, structures representing carbocyclic or heterocyclic rings include both " E " and " Z " isomers. Substituents around the carbocyclic or heterocyclic ring may also be referred to as "cis" or "trans", where the term "cis" refers to the substituent on the same side of the plane of the ring and "trans"Lt; / RTI > on the opposite side of the plane of FIG. A mixture of compounds in which the substituent is placed on both the same side and the opposite side of the plane of the ring is denoted "cis / trans."

The individual enantiomers and diastereoisomers of the compounds of the present invention may be prepared from commercially available starting materials comprising asymmetric or stereoisomeric centers or by methods known to those skilled in the art following preparation of the racemic mixture . ≪ / RTI > These redissolving methods include (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resultant mixture of diastereomers by recrystallization or chromatography, and a glass of optically pure product from the auxiliary material, (2) (3) direct separation of a mixture of optical enantiomers on a chiral liquid chromatography column, or (4) kinetic partitioning of the reaction using a stereoselective chemical or enzymatic reaction agent. The racemic mixtures may be separated into their component enantiomers by well known methods such as crystallization of the compounds in chiral solvents or by chiral-phase gas chromatography. Stereoselective synthesis, chemical or enzymatic reactions in which a single reactant forms a different mixture of stereoisomers during the formation of a new stereocenter or during the conversion of stereocenters that have existed before are well known in the art. Stereoselective synthesis methods include both enantiomer- and diastereoselective conversion. For this, reference can be made, for example, to Carreira and Kvaerno, Classics in Stereoselective Synthesis , Wiley-VCH: Weinheim, 2009.

The compounds disclosed herein may exist in solvated as well as unsolvated forms by means of pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is to be understood that the present invention includes both solvated and unsolvated forms It is intended to include both. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In one embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in crystalline form.

The present invention contemplates the use of the same isotopically enriched isotypes of the present invention as those recited herein except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number, Compounds are also covered. Examples of isotopes that may be included in the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N , 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively. For example, the compounds of the present invention may have one or more H atoms substituted with deuterium.

Certain isotopically-labeled labeled compounds (eg, compounds labeled with 3 H and 14 C) can be used for compound and / or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of manufacture and detectability. In addition, substitution with heavy isotopes such as deuterium (i.e., 2 H) may provide certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage conditions) resulting from greater metabolic stability, Therefore, it may be desirable in a few situations. The isotopically labeled compounds of the present invention can generally be prepared by the following procedure analogous to that described in the examples herein by replacing the non-isotopically labeled reagent with an isotope labeled reagent have.

The term "precursor " refers to a compound that is modified in vivo to produce a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof. Deformation may occur by a variety of mechanisms (e. G., By esterase, amidase, phosphatase, oxidative and / or reductive metabolism) at various sites (e.g., intestinal lumen or intestinal, blood or liver passage) have. Precursors are well known in the art (see, for example, Rautio, Kumpulainen, et al. , Nature Reviews Drug Discovery 2008, 7, 255). For example, when the present compound or a compound pharmaceutically acceptable salt, hydrate or solvate of the invention contain carboxylic acid functional groups, the precursor, having cut the hydrogen atom of the acid group, a 4 to 9 carbon atoms (C 1 -C 8) alkyl, (C 2 -C 12) alkanoyloxymethyl, 1- (alkanoyloxy) ethyl 1-methyl-1 with characters, from 5 to 10 carbon atoms (alkanoyloxy) -ethyl, 3 to (Alkoxycarbonyloxy) ethyl having 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy) ethyl having 5 to 8 carbon atoms, alkoxycarbonyloxymethyl having 6 to 6 carbon atoms, (Alkoxycarbonyl) aminomethyl having 3 to 9 carbon atoms, 1- (N- (alkoxycarbonyl) amino) ethyl having 4 to 10 carbon atoms, 3-phthalidyl, 4- Di-N, N- (C 1 -C 2 ) alkylamino (C 2 -C 3 ) alkyl (eg, β-dimethylaminoethyl), (C 1 -C 2 ) alkyl, N, N-di (C 1 -C 2 ) alkylcarbamoyl- (C 1 -C 2 ) alkyl and piperidino-, pyrrolidino- or morpholino (C 2 -C 3 ) alkyl, and the like.

Similarly, if a compound of the present invention contains an alcohol functional group, the precursor, a hydrogen atom of the alcohol group, (C 1 -C 6) alkyl-carbonyl-oxy-methyl, 1 - ((C 1 -C 6) alkyl-carbonyl-oxy ) Ethyl, 1-methyl-1 - ((C 1 -C 6 ) alkylcarbonyloxy) ethyl, (C 1 -C 6 ) alkoxycarbonyloxymethyl, N- (C 1 -C 6 ) alkoxycarbonylamino methyl, succinate alkanoyl, (C 1 -C 6) alkylcarbonyl, amino-α- (C 1 -C 4) alkyl carbonyl, arylalkyl carbonyl, and α- amino-alkyl-carbonyl, α-, or amino alkyl carbonyl- aminoalkylcarbonyl wherein each alpha -aminoalkylcarbonyl group is a naturally occurring L-amino acid, P (O) (OH) 2 , -P (O) (O (C 1 -C 6 ) alkyl) 2 or glycosyl (a radical obtained by removing a hydroxyl group in the form of a hemiacetal of a carbohydrate), and the like.

If the compound of the present invention comprises an amine functional group, the precursor may be, for example, an amide or carbamate, an N-alkylcarbonyloxyalkyl derivative, an (oxodioxolenyl) methyl derivative, a N-Mannich base, Can be formed by the formation of an imine or an enamine. In addition, secondary amines can be metabolically cleaved to produce bioactive primary amines, or tertiary amines can be metabolically cleaved to produce bioactive primary or secondary amines. For this, see, for example,

Figure pct00002
, et al., Molecules 2008, 13 , 519] and references therein.

I. Tricyclic Compounds

In certain embodiments, the present invention provides a compound of formula I: And pharmaceutically acceptable salts, stereoisomers, esters, and precursors thereof.

(I)

Figure pct00003

Wherein,

D can be a 5-7 membered heterocyclic or heteroaromatic ring wherein one of the two atoms in common between ring B and ring D is nitrogen and the other is carbon;

B may be a 4-6 membered saturated or partially unsaturated heterocyclic ring; Wherein the B ring may be optionally substituted by one or more fluorine atoms on any one of the available carbon atoms;

X is + -C (R D1 R D2) - *, + -C (R C1) = *, + -N = *, + -C (R D1 R D2) -C (R D5 R D6) - *, + -C (R C1) = C (R C2) - *, + -W 1 -C (R D5 R D6) - *, + -W 1 -C (O) - *, + -C (R D1 R D2) -C (R D3 R D4 ) -C (R D5 R D6) - *, + -W 1 -C (R D3 R D4) -C (R D5 R D6) - *, + -W 1 -C (O) -C (R D5 R D6) - *, + -C (R D1 R D2) -W 2 -C (R D5 R D6) - *, + -C (R D1 R D2) -W 2 - C (O) - * itdoe be selected from the group consisting of; Where + and * represent attachment points of X as shown in formula I;

Y is * -CH 2 - #, * -CH 2 -CH 2 - #, * -CH 2 -CH 2 -CH 2 - #, * -CH 2 -O-CH 2 - can be selected from the group consisting of # Wherein * and # represent attachment points of Y as shown in formula (I);

W 1 can be selected from the group consisting of O or N (R N1 );

W 2 can be selected from the group consisting of O or N (R N2 );

A is phenyl, 5 to 6 membered heteroaryl having 1, 2 or 3 heteroatoms each selected from S, N or O, and 4 to 6 heteroatoms each having 1, 2 or 3 heteroatoms selected from N or O, 7 membered heterocycle;

R A1 for each occurrence can be independently selected from the group consisting of hydrogen, hydroxyl, cyano, halogen, C 1-4 alkyl or C 1-3 alkoxy; Wherein C 1-4 alkyl or C 1-3 alkoxy may be optionally substituted by one or more fluorines;

n can be 1 or 2;

R A2 can be selected from the group consisting of hydrogen, R i R j N-, heterocyclyl, heterocyclyloxy, heterocyclyl- (NR a ) -; Wherein said heterocyclyl may be optionally substituted with one or more substituents selected from R g ; Where said heterocyclyl comprises an -NH moiety, said nitrogen may be optionally substituted with one or more groups R h ; or

R A2 is selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 alkenyloxy, C 3-6 alkynyl oxy, C 3-6 cycloalkoxy, C 1-6 alkyl, -S (O) w - (wherein w is 0, 1 or 2), C 1-6 alkyl -N (R a) -, C 1-6 alkyl, -N (R a) - carbonyl -, C 1-6 alkylcarbonyl -N (R a) -, C 1-6 alkyl -N (R a) - carbonyl -N (R a) -, C 1-6 alkyl -N (R a) -SO 2 - , -SO 2 -N C 1-6 alkyl (R a) -, C 1-6 alkoxycarbonyl -N (R a) -, C 1-6 alkylcarbonyl -N (R a) -C 1-6 alkyl-, C 1-6 alkyl -N (R a) - carbonyl -C 1-6 alkyl-, C 1-6 alkoxy C 1-6 alkyl- ≪ / RTI > Wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 alkenyloxy, C 3-6 alkynyloxy, C 3-6 cycloalkoxy, C 1-6 alkyl, -S (O) w -, C 1-6 alkyl -N (R a) -, C 1-6 alkyl -N (R a) - carbonyl -, C 1-6 alkylcarbonyl -N (R a) -, C 1-6 alkyl -N (R a) - carbonyl -N (R a) -, C 1-6 alkyl -N (R a) -SO 2 -, C 1-6 alkyl, -SO 2 -N (R a) - , C 1-6 alkoxycarbonyl -N (R a) -, C 1-6 alkylcarbonyl -N (R a) C 1-6 Alkyl, -C 1-6 alkyl-N (R a ) -carbonyl-C 1-6 alkyl-, C 1-6 alkoxy-C 1-6 alkyl is R P , phenyl, phenoxy, heteroaryl, heteroaryl Optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, heteroaryl- (NR a ) -, heterocyclyl, heterocyclyloxy or heterocyclyl-N (R a ) -; Wherein said heteroaryl or phenyl can be optionally substituted with one or more substituents selected from R f , said heterocyclyl being optionally substituted with one or more substituents selected from R g ; When said heterocyclyl comprises an -NH moiety, said nitrogen may be optionally substituted by one or more groups R h ;

R D1 and R D2 may each independently be selected from the group consisting of hydrogen, fluorine, hydroxyl, C 1-2 alkyl or C 1-2 alkoxy; Wherein the C 1-2 alkyl and C 1-2 alkoxy may be optionally substituted with one or more fluorine atoms, or a group selected from cyano or hydroxyl;

R D3 and R D4 may each independently be selected from the group consisting of hydrogen, fluorine, hydroxyl, cyano, C 1-3 alkyl or C 1-3 alkoxy; Wherein said C 1-3 alkyl and C 1-3 alkoxy may be optionally substituted with one or more fluorine atoms, or a group selected from cyano, hydroxyl or N (R a R b );

R D5 and R D6 may each independently be selected from the group consisting of hydrogen, fluorine, hydroxyl, cyano, C 1-2 alkyl or C 1-2 alkoxy; Wherein C 1-2 alkyl and C 1-2 alkoxy may be optionally substituted with one or more fluorine atoms, or a group selected from cyano, hydroxyl or N (R a R b );

R C1 may be selected from the group consisting of hydrogen, halogen, C 1-2 alkyl or C 1-2 alkoxy; Wherein C 1-2 alkyl or C 1-2 alkoxy may be optionally substituted with one or more fluorine atoms;

R C2 can be selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C 1-2 alkyl or C 1-2 alkoxy; Wherein C 1-2 alkyl and C 1-2 alkoxy may be optionally substituted with one or more fluorine atoms, or a group selected from cyano, hydroxyl or N (R a R b );

R N1 may be selected from the group consisting of hydrogen or C 1-2 alkyl;

R N2 may be selected from the group consisting of hydrogen, C 1-3 alkyl or C 1-2 alkylcarbonyl; Wherein C 1-3 alkyl and C 1-2 alkylcarbonyl may be optionally substituted with one or more fluorine atoms, or a group selected from cyano, hydroxyl or N (R a R b );

R a and R b can be independently selected from the group consisting of hydrogen and C 1-3 alkyl for each occurrence; Wherein C 1-3 alkyl may be optionally substituted with one or more substituents selected from fluorine, cyano, oxo, and hydroxyl;

Or R & lt ; a & gt ; and R < b & gt ; may form, together with the nitrogen to which they are attached, a 4 to 6 membered heterocyclic ring which may bear an additional heteroatom selected from O, S or N; Wherein said 4 to 6 membered heterocyclic ring may be optionally substituted on carbon by one or more substituents selected from the group consisting of fluorine, cyano, oxo, or hydroxyl;

R f is, for each occurrence, R P, hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1 -6 alkoxy, C 1-6 alkyl, -S (O) w - (wherein w is 0, 1 or 2), C 1-6 alkylcarbonyl -N (R a) -; C 1-6 alkoxycarbonyl-N (R a ) -; Wherein R is selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkyl-S (O ) w- , C 1-6 alkylcarbonyl-N (R a ) -, C 1-6 alkoxycarbonyl-N (R a ) - may be optionally substituted with one or more substituents selected from R p ;

R g is, for each occurrence, R P, hydrogen, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkyl, -S (O) w - (wherein w is 0, 1 or 2), C 1-6 alkylcarbonyl -N (R a) -, C 1-6 alkoxycarbonyl -N (R a ) -; < / RTI > Wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkyl, -S (O) w -, C 1- 6 alkylcarbonyl-N (R a ) -, C 1-6 alkoxycarbonyl-N (R a ) - may be optionally substituted with one or more substituents selected from R P ;

R h is, for each case hydrogen, C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkyl, -S (O) 2 -, C 1-6 alkoxycarbonyl -, R i R j N- carbonyl -, R i R j N- SO 2 - doedoe independently selected from the group consisting of; Where C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkyl-S (O) 2- , C 1-6 alkylcarbonyl- R P may be optionally substituted with one or more substituents selected from;

R i and R j can be independently selected from the group consisting of hydrogen, C 1-4 alkyl and C 3-6 cycloalkyl for each occurrence; Wherein C 1-4 alkyl and C 3-6 cycloalkyl are optionally substituted with one or more substituents selected from fluorine, hydroxyl, cyano, R a R b N-, R a R b N-carbonyl-, C 1-3 alkoxy, Lt; / RTI >;

Or R i and R j, together with the nitrogen to which they are attached, fluorine, hydroxyl, oxo, cyano, C 1-6 alkyl, C 1-6 alkoxy, R a R b N-, R a R b N- SO 2 -, R a R b N- carbonyl-4, which may have an additional heteroatom selected from optionally, O, S or N substituted in the on-carbon by one or more substituents selected from the group consisting of to 7 Lt; RTI ID = 0.0 > heterocyclic < / RTI >ring; Wherein said C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with fluorine, hydroxyl or cyano; Which may be optionally substituted on the nitrogen by one or more substituents selected from the group consisting of C 1-6 alkyl, R a R b N-carbonyl-; Wherein said C 1-6 alkyl may be optionally substituted with fluorine, hydroxyl, or cyano;

R P is, for each occurrence, halogen, hydroxyl, cyano, C 1-6 alkoxy, R i R j N-, R i R j N- carbonyl -, R i R j N- SO 2 -, R i R j N-Carbonyl-N (R a ) -.

In some embodiments, X is + -C (R D1 R D2) - *, + -C (R C1) = *, + -N = *, + -C (R D1 R D2) -C (R D5 R D6) - *, + -OC (R D5 R D6) - *, + -N (R N1) -C (R D5 R D6) - *, + -OC (R D3 R D4) -C (R D5 R D6) - * itdoe be selected from the group consisting of; Where + and * represent attachment points of X as shown in formula I. Exemplary X moiety + -CH 2 - *, + -CH = *, + -N = *, + -OCH 2 - *, + NHCH 2 - * and + CH 2 CH 2 - selected from the group consisting of * Can be; Where + and * represent attachment points of X as shown in formula I.

In one embodiment, R D1 , R D2 , R C1 and R N1 can be independently selected from the group consisting of hydrogen and methyl for each occurrence. For example, R D1 , R D2 , R C1 and R N1 may be hydrogen.

In certain embodiments, R D3 , R D4 , R D5, and R D6 can be independently selected from the group consisting of hydrogen, fluorine, cyano, and C 1-2 alkyl for each occurrence. For example, R D3 , R D4 , R D5 and R D6 may be hydrogen.

In one embodiment, R C2 can be selected from the group consisting of hydrogen, halogen, cyano, and C 1-2 alkyl. For example, R C2 may be hydrogen.

In one embodiment, R N2 can be selected from the group consisting of hydrogen and C 1-2 alkyl. For example, R N2 may be hydrogen.

In certain embodiments, the D ring can be selected from the group consisting of:

Figure pct00004

Wherein * and # and + represent attachment points for the B ring and the phenyl ring as shown in formula (I). Exemplary D rings which may form part of an assumed tricyclic core are

Figure pct00005

≪ / RTI >

In some embodiments, Y can be selected from the group consisting of * -CH 2 - # , * -CH 2 -CH 2 - #, and * -CH 2 -O-CH 2 - # ; Where * and # denote attachment points for Y as shown in formula (I). For example, Y may be * -CH 2 -CH 2 - # ; Where * and # denote attachment points for Y as shown in formula (I).

For example, the B ring can, in certain embodiments, be selected from the group consisting of:

Figure pct00006

Wherein * and # represent attachment points for Y as shown in formula (I).

Exemplary B rings which may form part of an assumed tricyclic core may include:

Figure pct00007
.

In this specification, for example, tricyclic compounds represented by the general formulas Ia, Ib, Ic, Id, Ie, If, Ig and 1h are provided:

Figure pct00008

In certain embodiments, A may be phenyl.

Also, in the present specification, a compound represented by the following formula (II): And their pharmaceutically acceptable salts, stereoisomers, esters and precursors are provided:

≪ RTI ID = 0.0 &

Figure pct00009

Wherein,

D can be a 5-7 membered heterocyclic or heteroaromatic ring wherein one of the two atoms in common between ring B and ring D is nitrogen and the other is carbon;

B may be a 4-6 membered saturated or partially unsaturated heterocyclic heterocyclic ring; Wherein the B ring may be optionally substituted by one or more fluorine atoms on any one of the available carbon atoms;

X is + -C (R D1 R D2) - *, + -C (R C1) = *, + -N = *, + -C (R D1 R D2) -C (R D5 R D6) - *, + -C (R C1) = C (R C2) - *, + -W 1 -C (R D5 R D6) - *, + -W 1 -C (O) - *, + -C (R D1 R D2) -C (R D3 R D4 ) -C (R D5 R D6) - *, + -W 1 -C (R D3 R D4) -C (R D5 R D6) - *, + -W 1 -C (O) -C (R D5 R D6) - *, + -C (R D1 R D2) -W 2 -C (R D5 R D6) - *, + -C (R D1 R D2) -W 2 - C (O) - * itdoe be selected from the group consisting of; Where + and * represent attachment points of X as shown in formula I;

Y is * -CH 2 - #, * -CH 2 -CH 2 - #, * -CH 2 -CH 2 -CH 2 - #, * -CH 2 -O-CH 2 - can be selected from the group consisting of # He said; Wherein * and # represent attachment points of Y as shown in formula (I);

W 1 can be selected from the group consisting of O or N (R N1 );

W 2 can be selected from the group consisting of O or N (R N2 );

R A1 is independently selected from the group consisting of hydrogen, hydroxyl, cyano, halogen, C 1-4 alkyl or C 1-3 alkoxy for each occurrence; Wherein C 1-4 alkyl or C 1-3 alkoxy may be optionally substituted with one or more fluorines;

n can be 1 or 2;

R A2 can be selected from the group consisting of hydrogen, R i R j N-, heterocyclyl, heterocyclyloxy, heterocyclyl- (NR a ) -; Wherein said heterocyclyl can be optionally substituted with one or more substituents selected from R g ; If said heterocyclyl comprises an -NH moiety, said nitrogen may be optionally substituted with one or more groups R h ; or

R A2 is selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 alkenyloxy, C 3-6 alkynyl oxy, C 3-6 cycloalkoxy, C 1-6 alkyl, -S (O) w - (wherein w is 0, 1 or 2), C 1-6 alkyl -N (R a) -, C 1-6 alkyl, -N (R a) - carbonyl -, C 1-6 alkylcarbonyl -N (R a) -, C 1-6 alkyl -N (R a) - carbonyl -N (R a) -, C 1-6 alkyl -N (R a) -SO 2 - , -SO 2 -N C 1-6 alkyl (R a) -, C 1-6 alkoxycarbonyl -N (R a) -, C 1-6 alkylcarbonyl -N (R a) -C 1-6 alkyl-, C 1-6 alkyl -N (R a) - carbonyl -C 1-6 alkyl-, C 1-6 alkoxy C 1-6 alkyl- ≪ / RTI > Wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 alkenyloxy, C 3-6 alkynyloxy, C 3-6 cycloalkoxy, C 1-6 alkyl, -S (O) w -, C 1-6 alkyl -N (R a) -, C 1-6 alkyl -N (R a) - carbonyl -, C 1-6 alkylcarbonyl -N (R a) -, C 1-6 alkyl -N (R a) - carbonyl -N (R a) -, C 1-6 alkyl -N (R a) -SO 2 -, C 1-6 alkyl, -SO 2 -N (R a) - , C 1-6 alkoxycarbonyl -N (R a) -, C 1-6 alkylcarbonyl -N (R a) C 1-6 Alkyl, -C 1-6 alkyl-N (R a ) -carbonyl-C 1-6 alkyl-, C 1-6 alkoxy-C 1-6 alkyl is R P , phenyl, phenoxy, heteroaryl, heteroaryl aryloxy, heteroaryl, - (NR a) -, heterocyclyl, heterocyclyl-oxy or heterocyclyl -N (R a) - may optionally be substituted with; And wherein said heteroaryl or phenyl may be optionally substituted with one or more substituents selected from R f ; Said heterocyclyl may be optionally substituted with one or more substituents selected from R g ; If the heterocyclyl comprises an -NH moiety, the nitrogen may be optionally substituted with one or more groups R h ;

R D1 and R D2 may be independently selected from the group consisting of hydrogen, fluorine, hydroxyl, C 1-2 alkyl or C 1-2 alkoxy; Wherein the C 1-2 alkyl and C 1-2 alkoxy may be optionally substituted with one or more fluorine atoms, or a group selected from cyano or hydroxyl;

R D3 and R D4 may each independently be selected from the group consisting of hydrogen, fluorine, hydroxyl, cyano, C 1-3 alkyl or C 1-3 alkoxy; Wherein C 1-3 alkyl and C 1-3 alkoxy may be optionally substituted with a group selected from cyano, hydroxyl or N (R a R b );

R D5 and R D6 may each independently be selected from the group consisting of hydrogen, fluorine, hydroxyl, cyano, C 1-2 alkyl or C 1-2 alkoxy; Wherein the C 1-2 alkyl and C 1-2 alkoxy may be optionally substituted with one or more fluorine atoms, or a group selected from cyano, hydroxyl or N (R a R b );

R C1 may be selected from the group consisting of hydrogen, halogen, C 1-2 alkyl or C 1-2 alkoxy; Wherein C 1-2 alkyl or C 1-2 alkoxy may be optionally substituted with one or more fluorine atoms;

R C2 can be selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C 1-2 alkyl or C 1-2 alkoxy; Wherein the C 1-2 alkyl and C 1-2 alkoxy may be optionally substituted with one or more fluorine atoms, or a group selected from cyano, hydroxyl or N (R a R b );

R N1 may be selected from the group consisting of hydrogen or C 1-2 alkyl;

R N2 may be selected from the group consisting of hydrogen, C 1-3 alkyl or C 1-2 alkylcarbonyl; Wherein C 1-3 alkyl and C 1-2 alkylcarbonyl may be optionally substituted with one or more fluorine atoms or a group selected from cyano, hydroxyl or N (R a R b );

R a and R b can be independently selected from the group consisting of hydrogen and C 1-3 alkyl for each occurrence; Wherein C 1-3 alkyl may be optionally substituted with one or more substituents selected from fluorine, cyano, oxo, and hydroxyl;

Or R & lt ; a & gt ; and R < b & gt ; may form, together with the nitrogen to which they are attached, a 4 to 6 membered heterocyclic ring which may bear an additional heteroatom selected from O, S or N; Wherein the 4 to 6 membered heterocyclic ring may be optionally substituted on the carbon by one or more substituents selected from the group consisting of fluorine, cyano, oxo, or hydroxyl;

R f is, for each occurrence, R P, hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1 -6 alkoxy, C 1-6 alkyl, -S (O) w - (wherein w is 0, 1 or 2), C 1-6 alkylcarbonyl -N (R a) -; C 1-6 alkoxycarbonyl-N (R a ) -; Wherein R is selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkyl-S (O ) w- , C 1-6 alkylcarbonyl-N (R a ) -, C 1-6 alkoxycarbonyl-N (R a ) - may be optionally substituted with one or more substituents selected from R p ;

R g is, for each case R P, hydrogen, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1- 6 alkyl, -S (O) w - (wherein w is 0, 1 or 2), C 1-6 alkylcarbonyl -N (R a) -, C 1-6 alkoxycarbonyl -N (R a) - ≪ / RTI > Wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkyl, -S (O) w -, C 1- 6 alkylcarbonyl-N (R a ) -, C 1-6 alkoxycarbonyl-N (R a ) - may be optionally substituted with one or more substituents selected from R P ;

R h is, for each case hydrogen, C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkyl, -S (O) 2 -, C 1-6 alkoxycarbonyl -, R i R j N- carbonyl -, R i R j N- SO 2 - itdoe be independently selected from the group consisting of; Where C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkyl-S (O) 2- , C 1-6 alkylcarbonyl- R < P & gt ;;

R i and R j can be independently selected from the group consisting of hydrogen, C 1-4 alkyl and C 3-6 cycloalkyl for each occurrence; Wherein C 1-4 alkyl and C 3-6 cycloalkyl are optionally substituted with one or more substituents selected from fluorine, hydroxyl, cyano, R a R b N-, R a R b N-carbonyl-, C 1-3 alkoxy, ≪ / RTI >

Or R i and R j, together with the nitrogen to which they are attached, fluorine, hydroxyl, oxo, cyano, C 1-6 alkyl, C 1-6 alkoxy, R a R b N-, R a R b N- SO 2 -, R a R b N- carbonyl-4, which may have an additional heteroatom selected from optionally, O, S or N substituted in the on-carbon by one or more substituents selected from the group consisting of to 7 Lt; RTI ID = 0.0 > heterocyclic < / RTI >ring; Wherein said C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with fluorine, hydroxyl or cyano; Which may be optionally substituted on the nitrogen by one or more substituents selected from the group consisting of C 1-6 alkyl, R a R b N-carbonyl-; Said C 1-6 alkyl may be optionally substituted with fluorine, hydroxyl, or cyano;

R P is, for each occurrence, halogen, hydroxyl, cyano, C 1-6 alkoxy, R i R j N-, R i R j N- carbonyl -, R i R j N- SO 2 -, R i R j N-Carbonyl-N (R a ) -.

In certain embodiments, R A1 of the tricyclic compound of formula (II) can be selected from the group consisting of hydrogen, halogen, C 1-2 alkyl, C 1-2 alkoxy; Wherein C 1-2 alkyl may be optionally substituted with one or more fluorines. For example, R A1 can be hydrogen or fluorine.

In another embodiment, R A2 of the tricyclic compound of formula II is selected from the group consisting of hydrogen, R 1 R j N, heterocyclyl, C 1-6 alkyl, C 3-6 alkenyl, C 3-6 cycloalkyl, C 1 -6 alkoxy; < / RTI > Wherein said heterocyclyl can be optionally substituted with one or more groups R g wherein said heterocyclyl comprises an -NH moiety said nitrogen can be optionally substituted with one or more groups R h , ; The C 1-6 alkyl, C 3-6 alkenyl, C 3-6 cycloalkyl, and C 1-6 alkoxy may be optionally substituted with one or more groups R P. For example, R A2 is selected from the group consisting of 3- (N, N-diethylamino) propyl, 3- (pyrrolidin- Enyl, (Z) -3- (azetidin-1-yl) prop-1-enyl, Lt; / RTI >

(R) -7- [2- ((Z) -3-diethylaminoprop-1-enyl) -4-fluorobenzenesulfonyl-amino] -2,3,3a, 4 -Tetrahydro-lH-benzo [b] pyrrolo [l, 2-d] [l, 4] oxazine-6-carboxylic acid; (S) -7- [2 - ((Z) -3-diethylaminoprop-1-enyl) -4-fluorobenzenesulfonyl-amino] -2,3,3a, 4-tetrahydro- -Benzo [b] pyrrolo [1,2-d] [l, 4] oxazine-6-carboxylic acid; Dihydro-lH-pyrrolo [1,2-a] pyrimidin-7-ylmethyl) ] Indole-8-carboxylic acid; 7-Benzenesulfonylamino-2,3-dihydro-lH-pyrrolo [l, 2-a] indole-8-carboxylic acid; 7- [2 - ((Z) -3-diethylaminoprop-1-enyl) -4-fluorobenzenesulfonylamino] -2,3,9,9a-tetrahydro-lH- pyrrolo [ , 2-a] indole-8-carboxylic acid; (R) -7- [2 - ((Z) -3- diethylaminoprop-1-enyl) -4-fluorobenzenesulfonylamino] -2,3,9,9a-tetrahydro- Pyrrolo [l, 2-a] indole-8-carboxylic acid; (S) -7- [2- ((Z) -3-diethylaminoprop-1-enyl) -4-fluorobenzenesulfonylamino] -2,3,9,9a-tetrahydro- Pyrrolo [l, 2-a] indole-8-carboxylic acid; 7- [2 - ((Z) -3-diethylaminoprop-1-enyl) -4-fluorobenzenesulfonyl-amino] -1,2,3,3a, 4,5-hexahydropyrrolo [L, 2-a] quinoline-6-carboxylic acid; (R) -6- [2 - ((Z) -3-diethylaminoprop-1-enyl) -4-fluorobenzene-esulphonylamino] -1,2,2a, 3- tetrahydro- 4-oxa-8b-azacyclobuta [a] naphthalene-5-carboxylic acid; Dihydro-lH-benzo [d] pyrrolo [2,3-d] pyrimidin-4- 1,2-a] imidazole-5-carboxylic acid; And their pharmaceutically acceptable salts, stereoisomers, esters, and precursors.

The procedure for preparing the compounds described herein is provided below with reference to Schemes 1-2. In the reactions described below, it may be necessary to protect the reactive functional groups (e.g., hydroxyl, amino, thio or carboxyl groups) in order to avoid their unwanted participation in the reaction. The incorporation of such groups and the methods necessary to introduce and remove them are well known to those skilled in the art (see, e. G., Greene, Wuts, Protective Groups in Organic Synthesis. 2nd Ed. (1999)). The deprotection step may be a final step in the synthesis to remove the protecting group as disclosed herein, or to give a compound of formula (I), for example, as illustrated in the following general formula (I). The starting materials used in the following reaction schemes can be purchased or prepared by methods described in the chemical literature or by modifications thereof, using methods known to those skilled in the art. The procedure by which the steps are carried out may vary depending on the group to be introduced and the reagents used, but will be apparent to those skilled in the art.

The general synthetic strategy used to prepare the tricyclic compounds of general formula I is depicted in Scheme 1. The tricyclic system was assembled in various ways starting from the appropriately substituted and protected phenyl ring 1A. The group G 'may be a suitably protected carboxylic acid such as methyl- or tert -butyl carboxylate, or may be readily converted to a carboxylic acid such as nitrile or aldehyde. The group G is a functional group that can be subsequently converted to a sulfonamide group, or a sulfonamide group such as an appropriately protected aniline or the like. The B'-ring may be attached directly to the substituted phenyl group to give intermediate 1B, and the D'-ring may then be formed by an intramolecular reaction to give intermediate 1E. Alternatively, the B'-ring may be attached to the substituted phenyl intermediate product 1A via linker X 'to give intermediate product 1C, which can then be formed by an intramolecular reaction to give intermediate product 1E have. Alternatively, the D'-ring may be built on a substituted phenyl group to give intermediate 1D, followed by B'-ring assembly to give intermediate 1E. Modifications to the B 'and D' rings may be necessary to provide the required ring system, which may be performed before or after the formation of the tricyclic core. Compounds of formula I may be prepared from intermediate 1E by removal of any protecting groups. Alternatively, further modifications, such as modifications in G, etc. can be made to 1E, and then any protecting groups are removed to give compounds of general formula I. The specific steps of the synthesis process are described in more detail below.

Scheme 1

Figure pct00010

In step (i) of Scheme 1, the compound of structure 1A can be coupled to the compound of structure 1B 'under a range of conditions, wherein B' is a suitable ring to confer the compound of type 1B. The introduction of the B ' ring may require the preparation of many steps and many intermediates. Protectors may also be needed.

If R < 1 > is a suitable group (e.g., a halide or triflate), 1A can be converted to 1B by formation of a carbon-nitrogen bond. Carbon nitrogen bonds can be formed under a certain range of conditions. For example, 1A may be treated with palladium catalysts in a solvent (e.g., THF or toluene) (e. G., Palladium < In the presence of a phosphine (e.g., BINAP or tri- tert -butylphosphonium tetrafluoroborate) in the presence of a base (e.g., sodium tert -butoxide, acetate or tris- (dibenzylideneacetone) Or cesium carbonate). ≪ / RTI >

Alternatively, in step (i) of Scheme 1, the carbon-nitrogen bond may be removed by irradiation of the microwave at a temperature between room temperature and the reflux temperature of the solvent, or alternatively at a temperature of 120-180 & Optionally in the presence of a base (e.g. potassium carbonate or potassium phosphate) in the presence of a copper catalyst (e.g., copper or iodide) in a suitable solvent (e.g., DMPU, DMF or toluene) (Wherein R < 1 > is a suitable group (e.g., a halide or triflate) in the presence of a base, such as crown-6 or a ligand such as 1,10-phenanthroline or 1,4-diaminocyclohexane ). ≪ / RTI >

In step (iv) of Scheme 1, groups R < 2 > and R < 3 > of compound 1B may be joined together to give group X ', which forms a D'-ring. R 2 or R 3 may be masked by a protecting group during step (i) and may also require deprotection before group X 'can be formed. For example, if R < 2 > is a nitro group, the group may be hydrogenated using, for example, hydrogen in the presence of a suitable catalyst (e.g., palladium on a solid support such as carbon or the like); Or by treatment with an inorganic reducing agent (for example, tin (II) chloride in DMF) to give an amino group. For example, if R 2 or R 3 is a hydroxyalkyl group, the group may be treated with an oxidizing agent (such as Jones reagent or manganese dioxide) to give an aldehyde; Or another oxidizing agent (such as potassium permanganate) to give the carboxylic acid. For example, if R 2 or R 3 is an aldehyde, the group may be treated with an oxidizing agent (such as potassium permanganate) to give a carboxylic acid or treated with a reducing agent (such as sodium borohydride) to give an alcohol. For example, when R 2 or R 3 is a ketone, the group may be treated with a reducing agent (such as sodium borohydride) to give a secondary alcohol. For example, if R 2 or R 3 is a carboxylic acid or an ester, the group may be treated with a reducing agent (e.g. For example, if R 2 or R 3 is alkenyl, then the group may be treated with borane (eg, 9-borobicyclononane) and then oxidized with, for example, hydrogen peroxide to give a primary or secondary alcohol .

The formation of linker X ' can be carried out in various ways known to those skilled in the art. For example, if R 2 is hydroxyl and R 3 is -C (R D5 R D6 ) OH or -C (R D5 R D6 ) C (R D3 R D4 ) OH, then 1B is a phosphine (R D5 R D6 ) - or -OC (R D3 R D4 ) C (O), in the presence of a suitable base (e.g., diisopropyl azodicarboxylate) R D5 R D6 ) -.

Alternatively, the R 2 is hydroxyl, or -C (R R D1 D2) OH, R 3 is -C (R D5 R D6) L (where L is a leaving group (e.g., halogen, tosylate or triflate) , Then 1B is treated with a base such as diisopropylethylamine, potassium carbonate or sodium hydride to give 1E where X 'is -OC (R D5 R D6 ) - or -C (R D1 R D2 ) OC (R D5 R D6 ) -.

Alternatively, when R 2 is -C (R D1 R D2 ) L, where L is a leaving group such as a halogen, tosylate or triflate, and R 3 is -C (R D5 R D6 ) OH 1B is treated with a base such as diisopropylethylamine, potassium carbonate or sodium hydride to form 1E where X 'is -C (R D1 R D2 ) OC (R D5 R D6 ) - can do.

Alternatively, when R 2 is hydroxyl and R 3 is -C (R D5 R D6 ) C (R D3 R D4 ) L where L is a leaving group (eg, halogen, tosylate or triflate) , 1B is treated with a base (such as diisopropylethylamine, potassium carbonate or sodium hydride) to form 1E where X 'is -OC (R D3 R D4 ) C (R D5 R D6 ) - can do.

Alternatively, the R 2 is -C (R D1 D2 R) L, R 3 is a carboxylic acid, 1B, the base is treated with (e.g., diisopropylethylamine, potassium carbonate or sodium hydride) 1E (where, X 'Is -C (R D1 R D2 ) OC (O) -.

Alternatively, the R 2 is hydroxyl or -C (R R D1 D2) OH, R 3 is a carboxylic acid or carboxylic acid ester, 1B are acid (e.g., hydrochloride) or a dehydrating agent (e.g., dicyclohexylcarbodiimide or Acetic anhydride) to form 1E where X 'is -OC (O) - or -C (R D1 R D2 ) OC (O) -.

Alternatively, if R 2 is hydroxyl and R 3 is -C (R D5 R D6 ) CO 2 H, then 1B can be an acid such as hydrochloric acid or a dehydrating agent such as dicyclohexylcarbodiimide or acetic anhydride, To form 1E, wherein X 'is -OC (O) C (R D5 R D6 ) -.

Alternatively, the R 2 is hydroxyl or -C (R R D1 D2) OH, R 3 is a carboxylic acid, a carboxylic acid is preferred (e. G., By treatment with 2,4,6-trichloro benzoyl chloride ) Can be converted to the activated ester either as a mixed anhydride or by treatment with HATU (e.g., by treatment with HATU in the presence of a base such as diisopropylethylamine or pyridine, etc.) and the resulting mixed anhydride or activated ester can be converted to a base (O) - or -C (R D1 R D2 ) OC (O) -) in the presence of a base such as triethylamine or triethylamine.

Alternatively, if R 2 is hydroxyl and R 3 is -C (R D5 R D6 ) CO 2 H, the carboxylic acid can be converted first (eg, by treatment with 2,4,6- trichlorobenzoyl chloride ) Can be converted to the activated ester either as a mixed anhydride or by treatment with HATU (e.g., by treatment with HATU in the presence of a base such as diisopropylethylamine or pyridine, etc.) and the resulting mixed anhydride or activated ester can be converted to a base diisopropylethylamine, is further treated with ethyl amine, pyridine or potassium carbonate), 1E (where, X 'is -OC (O) CR D5 R D6 ) - may form a Im).

Alternatively, if R 2 is -NH (R N1 ) or -C (R D1 R D2 ) NH (R N2 ) and R 3 is a carboxylic acid, the carboxylic acid can be reacted , HATU and base, such as diisopropylethylamine or pyridine, or TBTU), and the resulting activated ester is further treated with a base to give 1E where X 'is -N ( N1 R) C (O) - may form a Im) - or -C (R D1 D2 R) N (R N2) C (O).

Alternatively, if R 2 is -NH (R N1 ) and R 3 is -C (R D5 R D6 ) CO 2 H, then the carboxylic acid can be reacted (for example, with HATU and base, (For example, by treatment with diisopropylethylamine or pyridine, or TBTU), and the resulting activated ester is further treated with a base to give 1E where X 'is -N (R N1 ) C ( O) C (R D5 R D6 ) -.

Alternatively, if R 2 is -NH (R N1 ) or -C (R D1 R D2 ) NH (R N2 ) and R 3 is a carboxylic acid, then 1B is treated with a dehydrating agent such as diisopropylcarbodiimide is, 1E (where, X 'is -N (R N1) C (O ) - Im - or -C (R D1 R D2) N (R N2) C (O)) can be formed.

Alternatively, if R 2 is -NH (R N1 ) and R 3 is -C (R D5 R D6 ) CO 2 H, then 1B is treated with a dehydrating agent (such as diisopropylcarbodiimide) Where X 'is -N (R N1 ) C (O) C (R D5 R D6 ) -.

Alternatively, in step (iv) of Scheme 1, R 2 is -NH (R N1), or -C (R R D1 D2) NH (R N2), and the -C (R D5 R D6) R 3 L (Wherein L is a leaving group such as a halogen, tosylate or triplet), 1B is treated with a base such as diisopropylethylamine, pyridine or potassium carbonate to give 1E, wherein X 'is -N (R N1 ) C (R D5 R D6 ) - or -C (R D1 R D2 ) N (R N2 ) C (R D5 R D6 ) -.

Alternatively, in step (iv) of Scheme 1, R 2 is -NH (R N1 ) and R 3 is -C (R D5 R D6 ) C (R D3 R D4 ) (R < 1 > ) C (R (1), where R & D3 R D4 ) C (R D5 R D6 ) -.

Alternatively, if one of the two groups R < 2 > or R < 3 > is an aldehyde and the other group is a phosphorane (e.g., alkyltriphenylphosphorane) or an alkylphosphonate (e.g., an alkylphosphonic acid diethyl ester) Is treated with a base such as diisopropylethylamine, potassium carbonate or sodium hexamethyldisilazide to form 1E where X 'is an alkene (-C (R C1 ) = C (R C2 ) -) .

Alternatively, if R 2 is -NH (R N1 ) or -C (R D1 R D2 ) NH (R N2 ) and R 3 is an aldehyde or ketone (-C (O) (R D5 ) (E.g. sodium cyanoborohydride) in the presence of a chlorinating solvent (e.g., 1,2-dichloroethane), optionally in the presence of an acid (e.g., acetic acid), at a temperature between room temperature and the reflux temperature of the solvent is treated with a hydride) as a fluoride or sodium tri acetoxy time signal, 1E (where, X 'is -N (R N1) CH (R D5) - or -C (R D1 D2 R) N (R N2) CH ( R D5 ) -.

Alternatively, if R 2 is -NH (R N1 ) and R 3 is an aldehyde or ketone (-C (R D5 R D6 ) C (O) (R D3 )), then 1B is at room temperature and the reflux temperature (E.g. sodium cyanoborohydride or sodium triacetoxyborohydride in the presence of a chlorinating solvent such as 1,2-dichloroethane, optionally in the presence of an acid such as acetic acid, is treated with rohayi deurayideu) 1E (where, X 'is -N (R N1) CH (R D3) C (R D5 R D6) - may form a Im).

Alternatively, if R 2 is -NH 2 and R 3 is oxo, then 1B can be treated with an acid (eg, p-toluenesulfonic acid) or a Lewis acid (such as tin tetrachloride) Is -N =).

In step (ii) of Scheme 1, the compound of structure 1A can be reacted with 1C 'to form linker X ' and confer the compound of structure 1C. Formation of linker X 'in compounds having structure 1C may require many steps and many intermediates to be prepared, and the use of protecting groups may also be required.

For example, if R 2 is a hydroxyl group and R 4 is -C (R D5 R D6 ) OH or -C (R D5 R D6 ) C (R D3 R D4 ) OH then 1A and 1C ' (R D5 R D6 ) - or -OC (R D3 R D4 ) in the presence of a reducing agent (e.g., triphenylphosphine) in the presence of a base (e.g., triphenylphosphine) ) C (R D5 R D6 ) -.

Alternatively, R 2 is hydroxyl or -C (R D1 R D2 ) OH and R 4 is -C (R D5 R D6 ) L where L is a leaving group (eg, halogen, tosylate or triflate) , Then 1'C and 1C'are treated with a base such as diisopropylethylamine, potassium carbonate or sodium hydride to give 1C where X 'is -OC (R D5 R D6 ) - or -C (R D1 R D2 ) OC (R D5 R D6 ) -.

Alternatively, when R 2 is hydroxyl and R 4 is -C (R D5 R D6 ) C (R D3 R D4 ) L where L is a leaving group (eg, halogen, tosylate or triflate) , 1A and 1C 'are treated with a base (such as diisopropylethylamine, potassium carbonate or sodium hydride) to give 1C, wherein X' is -OC (R D3 R D4 ) C (R D5 R D6 ) Can be formed.

Alternatively, in step (ii) of Scheme 1, if R 2 is -C (R D1 R D2 ) L and R 4 is a carboxylic acid, then 1A and 1C 'can be coupled to a base such as diisopropylethylamine, potassium carbonate Or sodium hydride) to form 1C (where X 'is -C (R D1 R D2 ) OC (O) -).

Alternatively, the R 2 is hydroxyl or -C (R R D1 D2) OH, R 4 is a carboxylic acid or carboxylic acid ester, 1A and 1C 'are acid (e.g., hydrochloride) or a dehydrating agent (e.g. dicyclohexyl carbonyl Diimide or acetic anhydride) to form 1C (where X 'is -OC (O) - or -C (R D1 R D2 ) C (O) -).

Alternatively, when R 2 is hydroxyl and R 4 is -C (R D5 R D6 ) CO 2 H, then 1A and 1C 'can be replaced by an acid (eg, hydrochloric acid) or a dehydrating agent (eg, dicyclohexylcarbodiimide or Acetic anhydride) to form 1C, where X 'is -OC (O) C (R D5 R D6 ) -.

Alternatively, in step (ii) of Scheme 1, wherein R 2 is hydroxyl or -C (R R D1 D2) OH, R 4 is a carboxylic acid, a carboxylic acid (e.g. thionyl chloride or oxalyl chloride (E.g. by treatment with 2,4,6-trichlorobenzoyl chloride in the presence of a base such as, for example, diisopropylethylamine, etc.) or in a mixed anhydride , By treatment with HATU in the presence of a base such as diisopropylethylamine or pyridine, or by treatment with diisopropylcarbodiimide in the presence of HOBT), followed by treatment with 1A and 1C Can be combined to form 1C, where X 'is -OC (O) - or -C (R D1 R D2 ) C (O) -.

Alternatively, in step (ii) of Scheme 1, if R 2 is hydroxyl and R 4 is -C (R D5 R D6 ) CO 2 H, the carboxylic acid may be converted to a carboxylic acid (for example, thionyl chloride or oxalyl chloride (For example by treatment with 2,4,6-trichlorobenzoyl chloride in the presence of a base such as, for example, diisopropylethylamine, or the like), or with mixed anhydrides For example, by treatment with HATU in the presence of a base such as diisopropylethylamine or pyridine, or by treatment with diisopropylcarbodiimide in the presence of HOBT), followed by reaction with 1A and 1C 'can be combined to form 1C, wherein X' is -OC (O) C (R D5 R D6 ) -.

Alternatively, if R 2 is -NH (R N1 ) or -C (R D1 R D2 ) NH (R N2 ) and R 4 is a carboxylic acid, then the carboxylic acid can be converted to the corresponding carboxylic acid by for example thionyl chloride or oxalyl chloride (E.g. by treatment with 2,4,6-trichlorobenzoyl chloride in the presence of a base such as, for example, diisopropylethylamine or the like) or as a mixed anhydride (by treatment with diisopropylethyl (By treatment with HATU in the presence of an amine or pyridine, or by treatment with diisopropylcarbodiimide in the presence of HOBT), then 1A and 1C 'can be combined to form 1C, where X' May form -N (R N1 ) C (O) - or -C (R D1 R D2 ) N (R N2 ) C (O) -).

Alternatively, if R 2 is -NH (R N1 ) and R 4 is -C (R D5 R D6 ) CO 2 H, then the carboxylic acid can be converted to a carboxylic acid (for example by treatment with thionyl chloride or oxalyl chloride) (For example, by treatment with 2,4,6-trichlorobenzoyl chloride in the presence of a base such as, for example, diisopropylethylamine or the like), or in a mixed anhydride (for example, by treatment with diisopropylethyl Can be converted to the activated ester by treatment with HATU in the presence of an amine or pyridine or by treatment with diisopropylcarbodiimide in the presence of HOBT and then 1A and 1C ''Can be -N (R N1 ) C (O) C (R D5 R D6 ) -.

Alternatively, if R 2 is -NH (R N1 ) or -C (R D1 R D2 ) NH (R N2 ) and R 4 is a carboxylic acid, then 1A and 1C 'are combined to form a dehydrating agent Carbodiimide) to form 1C (where X 'is -N (R N1 ) C (O) - or -C (R D1 R D2 ) N (R N2 ) C (O) -) .

Alternatively, if R 2 is -NH (R N1 ) and R 4 is -C (R D5 R D6 ) CO 2 H, then 1A and 1C 'are combined and reacted with a dehydrating agent such as diisopropylcarbodiimide To form 1E, wherein X 'is -N (R N1 ) C (O) C (R D5 R D6 ) -.

Alternatively, R 2 is -NH (R N1 ) or -C (R D1 R D2 ) NH (R N2 ) and R 4 is -C (R D5 R D6 ) L where L is a leaving group Halogen or triflate), then 1A and 1C 'are treated with a base such as diisopropylethylamine, pyridine or potassium carbonate to give 1C, where X' is -N (R N1 ) C (R D5 R D6 ) - or -C (R D1 R D2 ) N (R N2 ) C (R D5 R D6 ) -.

Alternatively, when R 2 is -NH (R N1 ) and R 4 is -C (R D5 R D6 ) C (R D3 R D4 ) L where L is a leaving group (eg, halogen or triflate) , Then 1 A and 1 C 'are treated with a base such as diisopropylethylamine, pyridine or potassium carbonate to give 1 C where X' is -N (R N1 ) C (R D3 R D4 ) C (R D5 R D6 ) -.

Alternatively, if R 2 is -NH (R N1 ) or -C (R D1 R D2 ) NH (R N2 ) and R 4 is an aldehyde or ketone (-C (O) (R D5 ) 1C 'is reacted with a reducing agent (e.g., sodium cyanoborohydride or sodium triacetoxyborohydride) in a chlorinating solvent (e.g., dichloromethane or 1,2-dichloroethane) at a temperature between room temperature and the reflux temperature of the solvent (R < 1 > ) CH (R D5 ) - or -C (R < D1 >) in the presence of an acid R D2 ) N (R N2 ) CH (R D5 ) -).

Alternatively, if R 2 is -NH (R N1 ) and R 4 is an aldehyde or ketone (-C (R D5 R D6 ) C (R D3 ) (O)) then 1A and 1C ' In the presence of a reducing agent (e.g., sodium cyanoborohydride or sodium triacetoxyborohydride) in a chlorinated solvent (e.g., dichloromethane or 1,2-dichloroethane) at a temperature between the reflux temperature of , Optionally in the presence of an acid such as acetic acid, to form 1C, wherein X 'is -N (R N1 ) CH (R D3 ) C (R D5 R D6 ) - .

Alternatively, if one of the two groups R < 2 > or R < 4 > is an aldehyde and the other group is a phosphorane (e.g., alkyltriphenylphosphorane) or an alkylphosphonate (e.g., an alkylphosphonic acid diethyl ester) 1C 'is treated with a base (such as diisopropylethylamine or potassium carbonate or sodium hexamethyldisilazide) to give 1C, wherein X is an alkene (-C (R C1 ) = C (R C2 ) -) .

Alternatively, if R 2 is a suitable leaving group (e.g., a halide or triflate) and R 4 is a terminal alkyne, then IA and 1C 'are reacted with a solvent (e.g., DMF) at a temperature between room temperature and the reflux temperature of the solvent. Optionally in the presence of a base (e.g. triethylamine) and in the presence of a palladium catalyst (e.g. tetrakis -triphenylphosphine palladium (0)), optionally in the presence of an additive (e.g. copper (I) Reacted together to form 1C, wherein X is an alkyne (-C = C-).

Alternatively, if R 2 is a leaving group (e.g., a halide or triflate) and R 4 is an alkynylstannane, then 1A and 1C 'are reacted with a solvent (e.g., DMF) at a temperature between room temperature and the reflux temperature of the solvent. (Wherein X is an alkyne (-C = C-)) in the presence of a palladium catalyst (e.g., bis -triphenylphosphine palladium chloride) Can be formed.

The intermediate product is alkynyl is, the solvent is reduced by hydrogenation in the presence of (e. G., Ethanol or ethyl acetate) catalyst (e.g., palladium on a solid carrier, such as carbon) of, 1C (where, X is -CH 2 CH 2 - Can be formed.

In step (v) of Scheme 1, the compound of structure 1E can be prepared from the compound of structure 1C by forming a carbon-nitrogen bond under various conditions. It may be necessary to remove any protecting group prior to the reaction to form the D'-ring.

For example, the carbon-nitrogen bond may be removed by irradiation of microwave at a temperature between room temperature and the reflux temperature of the solvent or alternatively at a temperature of 120-180 < 0 > C in a solvent (such as THF or toluene) BINAP or tri- tert -butylphosphonium tetrafluoroborate) and in the presence of a base (such as sodium tert -butoxide or cesium carbonate) in the presence of 1 C where R 1 is an appropriate group (e.g., a halide or triflate) Is treated with a palladium catalyst (e.g., palladium acetate or tris- (dibenzylideneacetone) -dipalladium) to form the compound of structure 1E.

Alternatively, in step (v) of Scheme 1, the carbon-nitrogen bond may be removed by irradiation of the microwave at a temperature between room temperature and the reflux temperature of the solvent, or alternatively at a temperature of 120-180 & (E.g., crown ethers such as 18-crown-6, or a ligand such as 1,10-phenanthrene, for example) in the presence of a base (e.g., potassium carbonate or potassium phosphate) in a suitable solvent (e.g., DMPU, DMF or toluene) (E.g., copper or copper iodide) in the presence of 1 C (where R < 1 > is a suitable group such as a halide or triflate) in the presence of a base Lt; RTI ID = 0.0 > 1E < / RTI >

In step (iii) of Scheme 1, the compound of structure 1A is a compound of structure 1D, wherein D 'is a 6- or 7-membered fused heterocyclic ring, and R 5 and R 6 form a B'-ring Lt; / RTI > is a suitable functional group that can be used in the process of the invention). Methods for forming bicyclic compounds of structure 1D from substituted phenyl rings of structure 1A are well known to those skilled in the art (see Comprehensive Heterocyclic Chemistry Ed .: Katritzky, Ramsden, Scriven, and Taylor, Elsevier, 2008 ).

The compounds of structure 1A can be converted to other compounds of structure 1A by modification of groups R < 1 > and / or R < 2 > to provide intermediates for the formation of compounds of structure 1D. For example, if R 1 is a nitro group or a protected amino group (e.g., a boc-protected amino group) and R 2 is a hydroxyl group, then 1A is reacted at a temperature between room temperature and the reflux temperature of the solvent (BrCH 2 C (O) R 6 ) in the presence of a base (e.g., potassium carbonate) in a suitable solvent (e.g., DMF) or DMF to yield a compound of structure IA where R 1 is a nitro or protected Is an amino group (e.g., a boc-protected amino group) and R 2 is an O-alkyl ketone (e.g., -CCH 2 C (O) R 6 ).

Alternatively, a compound of structure 1A, wherein R 1 is a nitro group or a protected amino group (e.g., a boc-protected amino group) and R 2 is a suitable group (e.g., a halide or a triflate) In the presence of a palladium catalyst (e.g., palladium acetate) in a solvent (e.g., acetonitrile or THF) at a temperature between the reflux temperature of the solvent, or alternatively at a temperature of 120 to 180 ° C, Is reacted with an alpha, beta -unsaturated ketone (e.g., vinyl ketone) in the presence of a base (e.g., triphenylphosphine or tri- o -tolylphosphine) and in the presence of a base Wherein R 1 is a nitro group or a protected amino group such as a boc-protected amino group and R 2 is an?,? -Unsaturated ketone (e.g., -CH = CHC (O) R 6 ) Can be given.

Alternatively, a compound of structure 1A wherein R < 1 > is a nitro group or protected amino group (e.g., boc-protected amino group) and R < 2 > is an aldehyde, for example, THF or DMF) of the base (e.g., sodium hydride or reacted with an alkyl ketone in the presence of potassium carbonate), the structure of the compound 1A (where R 1 is a nitro group or a protected amino group (e.g., boc- protected amino group ) And R 2 is an alpha, beta -unsaturated ketone (for example, -CH = CHC (O) R 6 ).

Alternatively, a compound of structure 1A wherein R < 1 > is a nitro group or a protected amino group (e.g., boc-protected amino group) and R < 2 > is an aldehyde, e.g., THF) of the base (e.g., diisopropylethylamine or ketone mixed phosphorane or alkylphosphonate and the reaction to give the compound of structure 1A in the presence of potassium carbonate) (wherein R 1 is a nitro group or a protected amino group ( (E.g., boc-protected amino group) and R 2 is an alpha, beta -unsaturated ketone (e.g., -CH = CHC (O) R 6 ).

Intermediate (wherein R 1 is a protected amino group (e.g., boc- protected amino group), and R 2 is, for α, β- unsaturated ketones (such as -CH = CHC (O) R 6 ) Im) may, for example, , a solvent (e.g., ethanol, ethyl acetate or dioxane) in the catalyst is further reduced by hydrogenation in the presence of (e. g. solid wall palladium on delay, such as carbon), the corresponding intermediates to (wherein, R 1 is a protected amino group (For example, a boc-protected amino group) and R 2 is an alkyl ketone (for example, -CH 2 CH 2 C (O) R 6 ).

Alternatively, a compound of structure 1A, wherein R 1 is a protected amino group (e.g., boc- or trifluoroacetyl-protected amino group) and R 2 is a suitable group (e.g., a halide or triflate) (Such as palladium acetate) and a base (e.g. palladium acetate) in a solvent (e.g., acetonitrile, THF or DMF) at a temperature between room temperature and the reflux temperature of the solvent or alternatively at a temperature of 120-180 & (e. g., triethylamine) with in the presence, optionally, to appropriately react with a substituted terminal acetylene in the presence of a copper salt (e.g., copper), different compounds of structure 1A (where R 1 is protected amino group (e.g., boc- or trifluoro-acetyl-protected amino group), and, R 2 is, for a substituted alkyne (for example, it is possible to give a -C = CR 6) Lim).

Alternatively, a compound of structure 1A, wherein R 1 is a protected amino group (eg, boc- or trifluoroacetyl-protected amino group) and R 2 is a suitable group (eg, a halide or triflate) (E.g., triphenylphosphine or tri- tert -butylphosphine) in a solvent (e.g., THF or dioxane) at a temperature between room temperature and the reflux temperature of the solvent or alternatively at a temperature of 120-180 & butyl phosphonium palladium catalyst tetrafluoroethylene in the presence of the baud rate) (e.g., palladium-tetrakis-triphenylphosphine or agent-less (dibenzylideneacetone) - dipalladium), as appropriate in the presence substituted alkynyl Stan I of To give a compound of structure 1A, wherein R 1 is a protected amino group (e.g., boc- or trifluoroacetyl-protected amino group), R 2 is a substituted alkyne -C = CR < 6 >).

A compound of structure 1A wherein R 1 is a nitro group or a protected amino group (e.g., boc-protected amino group) can be reacted to produce the corresponding compound wherein R 1 is an amino group For example, Logis may be reduced to an amino group by treatment with a metal or a metal salt (such as iron, zinc or tin chloride) of acid (e.g., hydrochloric acid or acetic acid). Alternatively, R 1 is a protected amino group (e.g., boc-protected amino group), the protecting group is removed by treatment with an acid in a solvent (e.g., dichloromethane or dioxane) at a temperature between room temperature and the reflux temperature of the solvent (e.g., trifluoroacetic acid or hydrogen chloride) .

In step (iii) of Scheme 1, a compound of structure 1A, wherein R 1 is an amino group and R 2 is a ketone containing group such as O-alkyl ketone such as -OC (R D5 R D6 ) C (O) R 6 or -OC (R D3 R D4) C (R D5 R D6) C (O) R 6 or alkyl ketones, for example -C (R D1 D2 R) C (R D3 D4 R) C (O) R 6 or -C (R D1 R D2 ) C (R D3 R D4 ) C (R D5 R D6 ) C (O) R 6 ) is reacted at a temperature between room temperature and the reflux temperature of the solvent, By treatment with a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride in the presence of an acid such as acetic acid in a suitable solvent such as 1,2-dichloroethane, of the compound (wherein X 'is -OC (R D5 R D6) -, -OC (R D3 D4 R) C (R D5 R D6) - -C (R D1 D2 R) C (R D3 D4 R) - or -C (R D1 D2 R) C (R D3 D4 R) C (R D5 R D6) - may be converted to Im).

Alternatively, in step (iii) of Scheme 1, a compound of structure 1A, wherein R 1 is a nitro group and R 2 is a ketone containing group such as an O-alkyl ketone such as -OC (R D5 R D6 ) C (O) R 6 or -OC (R D3 R D4) C (R D5 R D6) C (O) R 6 or alkyl ketones such as -C (R D1 D2 R) C (R R D3 D4 ) C (O) R 6 or -C (R D1 D2 R) C (R D3 D4 R) C (R D5 R D6) -C (O) R 6), Im), the solvent (e.g., ethanol or ethyl acetate ), In the presence of a metal catalyst (such as palladium on a solid support such as carbon), the compound of structure 1D wherein X 'is -OC (R D5 R D6 ) -, -OC (R D3 R D4 ) C (R D5 R D6) - -C (R D1 D2 R) C (R D3 D4 R) - or -C (R D1 D2 R) -C (R D3 D4 R) C (R D5 R D6) - Lt; / RTI >

Alternatively, in step (iii) of Scheme 1, the compound of structure 1A, wherein R 1 is a protected amino group (e.g., acetamide or trifluoroacetamide) and R 2 is a substituted alkyne, Palladium tetrakis- (triphenylphosphine) palladium in a solvent (e.g., acetonitrile or NMP) at a temperature between the reflux temperature of the solvent and the reflux temperature of the solvent, or alternatively by microwave irradiation at a temperature of 120-180 & (Such as potassium carbonate, cesium carbonate or potassium tert -butoxide) in the presence of a copper catalyst (for example, potassium iodide) or a tris- (dibenzylidene) -dipalladium) Lt; / RTI > can be converted to a compound of structure 1D, wherein X 'is-CH = by treatment with

A compound of structure 1D, wherein X 'is -CH =, can be converted to a compound of another structure 1D, wherein X' is -CH 2 -, by treatment with a reducing agent. For example, a compound of structure 1D (wherein X 'is -CH =) can be prepared by using a palladium catalyst (for example, palladium on solid support such as carbon or palladium hydroxide) in a solvent such as ethanol or ethyl acetate by the hydrogenation, a compound of structure 1D (where X 'is -CH 2 - Im) can be given. Alternatively, a compound of structure 1D, wherein X 'is -CH =, can be prepared by reacting a compound of formula IX with a suitable base such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride in a solvent such as acetic acid or trifluoroacetic acid, the compounds of structure 1D by treatment with a reducing agent such as (where X 'is -CH 2 - Im) may be converted to.

In step (vi) of Scheme 1, a compound of structure 1D can be converted to a compound of structure 1E by reaction between groups R < 5 > and R < 6 & gt ;, which form a B'-ring. In some cases, denaturation to the R < 5 > and R < 6 > groups in 1D may be required to produce the required ring system. It will be appreciated by those skilled in the art that various functional groups may be protected prior to the reaction or it may be necessary to remove protecting groups already present prior to the reaction.

For example, in step (vi) of Scheme 1, R 5 is H and R 6 is a leaving group such as -CH 2 CH 2 L, -CH 2 CH 2 CH 2 -L, or -CH 2 CH 2 CH 2 CH 2 L where L is a leaving group (e.g., a halide or a sulfonate, such as a mesylate or a tosylate), then 1 D can be removed at a temperature between room temperature and the reflux temperature of the solvent (E.g., sodium hydride, sodium methoxide or potassium carbonate) in a suitable solvent such as THF or DMF to afford the compound of structure 1E, wherein the B'-ring is azetidine, pyrrolidine or piperidine have.

Alternatively, in step (vi) of Scheme 1, R 5 is a leaving group such as -CH 2 CH 2 L, -CH 2 CH 2 CH 2 -L, or -CH 2 CH 2 CH 2 CH 2 L Wherein L is an alkyl group substituted with a leaving group (e.g., a halide such as bromide or iodide) and R 6 is a benzenesulfonyl group, 1D can be prepared by reacting a compound of formula In a solvent such as toluene under a radical condition such as tributyl tin hydride and azo- bis -isobutyryronitrile to give a compound of structure 1E wherein the B'-ring is azetidine, pyrrolidine or Peridine) can be given.

Alternatively, in step (vi) of Scheme 1, R 5 is CH 2 CH 2 OH and R 6 is CH 2 L, wherein L is a leaving group (eg, a halide or sulfonate, such as mesylate or (E.g. dichloromethane, THF or DMF) at a temperature between room temperature and the reflux temperature of the solvent, if R < 5 > is CH 2 CH 2 L and R 6 is CH 2 OH, Can be treated with a base (e.g., diisopropylethylamine, potassium carbonate or sodium hydride) in the presence of a base to give compounds of structure 1E, wherein the B'-ring is morpholine.

In step (vii) of Scheme 1, the compound of general structure 1E can be converted to a compound of general formula I by conversion of the group G 'to a carboxylic acid. If group G 'is a carboxylic acid ester (e. G., Methyl, tert -butyl or benzyl ester), various reagents and conditions can be used to convert 1E to a compound of general formula (I). For example, if G 'is a methyl, ethyl or benzyl ester, it may be dissolved in a solvent (such as methanol, dioxane, or the like) by irradiation with microwave at a temperature between room temperature and the reflux temperature of the solvent, (E.g., lithium hydroxide or sodium hydroxide) in a suitable solvent (e.g., water, or water, or mixtures thereof). Alternatively, if G ' is a benzyl ester, it can be converted to the carboxylic acid by hydrogenation in the presence of a catalyst (e.g., palladium on a solid support such as carbon, etc.) in a solvent such as dioxane or ethyl acetate. Alternatively, if the G ' group is a tert -butyl ester, it can be converted to the carboxylic acid by treatment with an acid in a solvent (e.g., dichloromethane or dioxane) (e.g., trifluoromethanesulfonic acid or hydrogen chloride).

Alternatively, if the group G 'is nitrile, treatment with an aqueous acid (e. G., A mineral acid such as hydrochloric acid) under suitable conditions (e. G., In heating, e.g., at reflux); Or may be converted to the carboxylic acid by treatment with an aqueous base (e.g., aqueous hydroxide, such as aqueous sodium hydroxide) under suitable conditions (e.g., heating, e.g., at reflux).

Alternatively, if group G 'is an aldehyde or hydroxymethyl moiety, it can be converted to a carboxylic acid by treatment with a suitable oxidizing agent (e. G. Potassium permanganate or chromic acid).

A general synthetic strategy to denature the group is depicted in Scheme 2. The G group may be introduced and / or denatured before, during, or after the assembly of the tricyclic ring system. The specific steps used to assemble the sulfonamide are described in more detail below.

Scheme 2

Figure pct00011

In Scheme 2, an asterisk indicates the presence of groups R 1 and R 2 (shown in Scheme 1) or the presence of an intermediate product (shown in Scheme 1) for the preparation of D 'and B'-rings, or rings.

In step (i) of Scheme 2, the compound of structure 2A, wherein G is a nitro group, may be reduced by reduction, for example, in a solvent such as an ether such as tetrahydrofuran or an alcohol such as methanol or ethanol, Can be converted to compound 2B by catalytic hydrogenation in the presence of a heavy metal catalyst (e. G., Palladium on a solid support such as carbon, etc.). Alternatively, compounds of structure 2A in which G is nitro may be converted to compounds of structure 2B by chemical reduction. For example, the reduction can be achieved using a metal or metal salt (e.g., iron, zinc or tin (II) chloride) in the presence of an acid (e.g., hydrochloric acid or acetic acid).

In step (i) of scheme 2, the compound of structure 2A, wherein G is a protected amino group, may be converted to a compound of structure 2B by removal of the protecting group. Protecting groups for amino groups are well known to those skilled in the art and their removal methods are equally well known (see, e. G., Greene, Wuts, Protective Groups in Organic Synthesis. 2nd Ed. (1999)). For example, compounds of structure 2A, wherein G is an amino group protected with one or two Boc groups, may be subjected to treatment with an acid in a solvent such as dichloromethane or dioxane (e.g., trifluoroacetic acid, formic acid, or hydrogen chloride) 0.0 > 2B < / RTI >

Alternatively, in step (i) of Scheme 2, the compound of structure 2A, wherein G is pivalo-protected aniline, may be reacted with an acid in a solvent (e.g., methanol) at a temperature between room temperature and the reflux temperature of the solvent ) Can be converted to the compound of structure 2B.

In step (ii) of Scheme 2, the compound of structure 2B is reacted with a suitable base in a suitable solvent (e.g., dichloromethane or dimethylformamide) at a temperature between room temperature and the reflux temperature of the solvent (E.g., substituted or unsubstituted benzenesulfonyl chloride) or an activated sulfonate ester (e.g., pentafluorophenylsulfonate ester) in the presence of a suitable base (e.g., ethylamine or cesium carbonate) 2C. ≪ / RTI >

Any of the compounds of formula I as depicted above, or, for example, compounds of general formula I, or intermediates described in the above schemes, may also be further derivatized using one or more standard synthetic methods known to those skilled in the art. Such methods may involve substitution, oxidation or reduction reactions. These methods can be used to obtain or modify the compounds of general formula I, or any preceding intermediates, by modifying, introducing or removing suitable functional groups. Specific substitution approaches include alkylation, arylation, heteroarylation, acylation, thioacylation, halogenation, sulfonylation, nitration, formylation, hydrolysis and coupling procedures. These procedures include introducing a functional group on the parent molecule (e.g., nitrification or sulfonylation of an aromatic ring), coupling two molecules together (e.g., coupling an amine to a carboxylic acid to give an amide, or To form a carbon-carbon bond between two heterocycles. For example, the alcohol or phenol group may be removed in a solvent (e.g. tetrahydrofuran) in the presence of a phosphine (e.g. triphenylphosphine) and a dehydrating agent (e.g. diethyl, diisopropyl or dimethyl azodicarboxylate) The phenol can be converted to an ether group by coupling with an alcohol. Alternatively, the ether group can be prepared by the addition of an alkylating agent (such as an alkyl halide or alkyl sulfonate) followed by proton removal of the alcohol with a suitable base (e.g., sodium hydride).

In another example, a primary or secondary amine can be alkylated using a reactive alkylation procedure. For example, the amine may be reacted with an aldehyde and / or an aldehyde in the presence of an acid (e.g. in the presence of acetic acid), in a solvent (e.g., a halogenated hydrocarbon such as dichloromethane or an alcohol such as ethanol) (E.g., sodium triacetoxyborohydride or sodium cyanoborohydride) in the presence of a base.

In another example, the hydroxy group (including the phenolic OH group) may be protected with a halogen atom or a sulfonyloxy group (e.g., alkylsulfonyloxy, e.g., trifluoromethanesulfonyloxy, or Arylsulfonyloxy, such as p-toluenesulfonyloxy), and the like. For example, aliphatic alcohols may be reacted with thionyl chloride in a halogenated hydrocarbon (such as dichloromethane) to give the corresponding alkyl chloride. A base (e.g., triethylamine) may also be used in the reaction.

In another example, the ester group can be converted to the corresponding carboxylic acid by acid- or base-catalyzed hydrolysis according to the properties of the corresponding ester group. Acid catalyzed hydrolysis can be achieved by treatment with organic or inorganic acids such as mineral acids in a solvent such as trifluoroacetic acid or dioxane in an aqueous solvent such as hydrochloric acid. Base-catalyzed hydrolysis can be achieved by treatment with an alkali metal hydroxide (e. G., Aqueous alcohol, e. G., Lithium hydroxide in methanol).

In another example, the aromatic halogen substituent in the compound is reacted with a base (e. G., Lithium base, such as n-butyl or tert -butyllithium) in a solvent such as tetrahydrofuran at low temperature And the mixture can then be quenched with an electrophile to introduce the desired substituent. Thus, for example, the formyl group can be introduced using dimethylformamide as the electrophile. The aromatic halogen substituent can also be subjected to a palladium catalyzed reaction to introduce groups such as, for example, carboxylic acid, ester, cyano or amino substituents.

In another example, a palladium-catalyzed coupling reaction is carried out on a wide range of substrates to aryl or heteroaryl rings substituted with a suitable leaving group (e.g., halogen or sulfonyl ester, e.g. triflate) to form a carbon-carbon bond . For example, the Heck reaction can be carried out in a suitable solvent (e.g., THF or DMF) at a temperature between room temperature and the reflux temperature of the solvent in the presence of a base (e.g., potassium carbonate or a tertiary amine, ligand in the presence of ethylamine) (e. g., phosphine, for example, organic palladium complexes in the presence of triphenyl phosphine) (for example, tetrakis- (triphenylphosphine) palladium, palladium (II) acetate or palladium (II ) Chloride) can be used to couple this ring system to the alkene (which may be further substituted or unsubstituted). In another example, the Sonogashira reaction is carried out in the presence of a base (e. G., Potassium carbonate or a tertiary amine, e. G., Potassium carbonate or potassium carbonate) in a suitable solvent (e. G., THF or DMF) at a temperature between room temperature and the reflux temperature of the solvent. By treatment with a palladium complex (such as tetrakis- (triphenylphosphine) palladium) and a halide salt of copper (I) (e.g. copper (I) iodide) in the presence of a base (Which may be further substituted or unsubstituted). In another example, the Stille reaction is carried out in the presence or absence of a salt (e.g., copper (I) halide) in a suitable solvent (e.g., dioxane or DMF) at a temperature between room temperature and the reflux temperature of the solvent. (E.g., alkenyl tin or alkynyl tin reagents, such as alkenyl tributylstannane) in the presence of a complex (e.g., tetrakis- (triphenylphosphine) palladium (0) Can be used to couple such ring systems to alkenes or alkynes.

Particular oxidation approaches include dehydrogenation and aromatization, decarboxylation and addition of oxygen to the desired functional groups. For example, aldehyde groups can be prepared by oxidation of the corresponding alcohol using conditions well known to those skilled in the art. For example, the alcohol may be treated with an oxidizing agent (e.g., Dess-Martin periodinane) in a solvent such as a halogenated hydrocarbon such as dichloromethane. Alternative oxidation conditions may be employed, such as treatment with oxalyl chloride and an active amount of dimethylsulfoxide followed by quenching by addition of an amine (e. G., Triethylamine). This reaction can be carried out in a suitable solvent (e.g., a halogenated hydrocarbon such as dichloromethane) and under suitable conditions (e.g., cooling to room temperature, e.g., -78 C followed by room temperature). In another example, the sulfur atom may be reacted with an oxidizing agent (e.g., peroxy acid, e.g., 3-chloroperoxybenzoic acid) in the presence of an inert solvent (e.g., a halogenated hydrocarbon such as dichloromethane) Sulfoxide or sulfone.

Specific reduction approaches include removal of oxygen atoms from certain functional groups or saturation (or partial saturation) of unsaturated compounds including aromatic or heteroaromatic rings. For example, the primary alcohol may be produced from the corresponding ester or aldehyde by reduction using a metal halide (e.g., lithium aluminum hydride or sodium borohydride in a solvent such as methanol or the like). Alternatively, the CH 2 OH group may be produced from the corresponding carboxylic acid by reduction using a metal halide (e.g., aluminum hydride in a solvent such as THF). In another example, the nitro group can be removed by catalytic hydrogenation in the presence of a metal catalyst (e.g., palladium on a solid support such as carbon, etc.) in a solvent (e.g., ether, e.g. THF or an alcohol, , Or by chemical reduction with a metal (e.g., zinc, tin or iron) in the presence of an acid such as acetic acid or hydrochloric acid. In a further example, the amine is reacted in the presence of a metal catalyst (solid support, for example palladium on carbon or Raney nickel, etc.) in a solvent (e.g. THF) By cooling to room temperature or below, for example, cooling to -78 [deg.] C, or heating under reflux, for example).

Salts of the compounds of general formula I can be prepared by reacting a compound of general formula I with a suitable acid or base and a suitable solvent or mixture of solvents (e. G., Ether, e. G., Diethyl ether or alcohol, e. G. Ethanol, By using a conventional procedure. Salts of the compounds of general formula I can be exchanged for other salts, for example, by treatment with conventional ion-exchange chromatography procedures, using methods known to those skilled in the art.

When it is desired to obtain certain enantiomers of the compounds of general formula I this may be prepared from the corresponding mixtures of the enantiomers using any suitable conventional procedure for resolving the enantiomers known to those skilled in the art. For example, diastereomeric derivatives (e. G., Salts) may be prepared by reaction of a mixture of enantiomers of a compound of general formula I (e. G., Racemates) with an appropriate chiral compound have. The diastereoisomers may then be separated by any conventional means such as crystallization or chromatography and the desired enantiomer is recovered (e. G., By treatment with an acid if the diastereomer is a salt). Alternatively, the racemic mixture of esters can be degraded by kinetic hydrolysis using a danganese biocatalyst (see, for example, Patel Steroselective Biocatalysts , Marcel Decker, New York 2000).

In other degradation processes, racemates of compounds of general formula I can be separated using chiral high performance liquid chromatography. Alternatively, a particular enantiomer can be obtained by using an appropriate chiral intermediate product in one of the methods described above. Chromatography, recrystallization and other conventional separation procedures can also be used with the intermediate or final product if desired to obtain the particular geometric isomers of the present invention.

II. Way

Another method of the invention provides a method of modulating the activity of MetAP2. Such methods include exposing the receptor to a compound described herein. In some embodiments, the compound used by one or more of the above methods is a compound of the general formula I, Ia, Ib, Ic, Id, Ie, If, Ig or II, Lt; / RTI > The ability of the compounds described herein to modulate or inhibit MetAP2 may be evaluated by procedures known to those skilled in the art and / or described herein. Another aspect of the invention provides a method of treating a disease associated with MetAP2 expression or activity in a patient. For example, the proposed method establishes the inhibition of intracellular MetAP2 which is effective in increasing thioredoxin production in a patient, for example, by administering a compound disclosed in an amount insufficient to reduce angiogenesis in a patient, Administering the disclosed compounds in an amount sufficient to induce multicenter stimulation of the anti-obesity process.

In certain embodiments, the invention provides a method of treating or ameliorating obesity in a patient by administering an effective amount of the disclosed compounds. Also provided herein is a method of introducing weight loss in a patient in need of weight loss. The assumed patient includes not only humans but also other animals, companion animals (for example, dogs and cats).

Other contemplated therapeutic methods include methods of treating or alleviating an obesity-related condition or co-morbidy by administering to a subject a compound as disclosed herein. For example, a method of treating Type 2 diabetes in a patient in need of treatment is contemplated herein.

Exemplary co-morbid diseases or other disorders that can be treated by the disclosed compounds include cardiac disorders, endocrine disorders, respiratory disorders, liver disorders, skeletal disorders, psychiatric disorders, metabolic disorders, metabolic disorders and reproductive disorders.

Exemplary cardiac disorders include hypertension, dyslipidemia, ischemic heart disease, cardiomyopathy, myocardial infarction, stroke, venous thromboembolic disease, and pulmonary hypertension. Exemplary endocrine disorders include type 2 diabetes and latent autoimmune diabetes in adults. Exemplary respiratory disorders include obesity-hypovolemia syndrome, asthma and obstructive sleep apnea syndrome. Exemplary liver disorders are nonalcoholic fatty liver disease. Exemplary skeletal disorders include back pain and osteoarthritis of the weight-bearing joint. Exemplary metabolic disorders include Prader-Willi Syndrome and Polycystic Ovary Syndrome. Exemplary reproductive disorders include sexual dysfunction, erectile dysfunction, infertility, obstetric complications, and fetal abnormalities. Exemplary psychiatric disorders include weight-related depression and anxiety.

In particular, in certain embodiments, the invention provides a method of treating a subject suffering from a disease or condition that requires treatment, comprising administering a therapeutically effective amount of a compound described herein, such as a compound of formula I, Ia, Ib, Ic, Id, Ie, If, Comprising administering to the subject an effective amount of a compound of the invention.

Obesity or "overweight" refers to excess fat in proportion to the lean body mass. Excess fat accumulation is associated with an increase in size (hyperplasia) as well as the number of adipose tissue cells (hyperplasia). Obesity is measured variously in terms of absolute weight, weight: height ratio, subcutaneous fat distribution, and social and aesthetic standards. A common measure of body fat is the Body Mass Index (BMI). BMI means the ratio of weight (expressed in kilograms) to the square of the key (expressed in meters). Body mass index can be calculated accurately using formula: body weight (kg) / key 2 (m 2) (SI) or 703 × body weight (lb) / key 2 (in 2 ) (US).

According to the Centers for Disease Control and Prevention (CDC), overweight adults have a BMI of 25 kg / m2 to 29.9 kg / m2, and obese adults have a BMI of 30 kg / m2 or more. BMI over 40 ㎏ / ㎡ is an index of morbidity or high obesity. Obesity may also refer to a patient having a waist circumference of about 102 cm for a male and about 88 cm for a female. For children, the definition of overweight and obesity considers the effects of age and sex on body fat. Patients with different genetic backgrounds may consider "obesity" considered at a different level than the general guidelines above.

The compounds of the present invention may also be useful for reducing the risk of secondary outcome of obesity, such as reducing the risk of left ventricular hypertrophy. For example, a method of treating a patient at risk for obesity, such as an overweight patient with a BMI of about 25 to 30 kg / m < 2 > In certain embodiments, the patient is a human.

BMI does not take into account the fact that excess fat may selectively occur in other parts of the body and that the occurrence of fatty tissue may be more dangerous than health in some parts of the body, rather than its and other parts of the body. For example, "central obesity", typically associated with the "apple-shaped" body type, is caused by excess fat in the abdominal region, particularly in the abdomen, including abdominal and visceral fat, Quot; peripheral obesity "that is typically associated with a " western " shaped body shape. Measurements of the ratio of waist / hip circumference ratio (WHR) can be used as an indicator of central obesity. The minimum WHR that represents central obesity has been varied and the central obesity population typically has a WHR of about 0.85 or more for women and about 0.9 or more for men.

A method for determining whether a patient is overweight or obese by taking into account the ratio of excess fat tissue to fat-free body mass includes obtaining the body composition of the patient. Body composition can be obtained by measuring the thickness of subcutaneous fat in various parts of the body, such as the abdominal region, subscapular region, arms, buttocks and thighs. These measurements are then used to estimate the total body fat with an error margin of approximately 4% points. Another method is bioelectrical impedance analysis (BIA), which uses the resistance of the current through the body to estimate body fat. Another method is to use a large water tank to measure body buoyancy. As body fat increases, buoyancy increases, while muscle mass tends to decrease.

In another aspect, the present invention provides a method for the treatment of obesity comprising measuring a level of at least one biomarker in relation to a subject being overweight or obese, and administering an effective amount of the disclosed compound to achieve a target level in the subject , A method for treating an overweight or obese subject. Exemplary biomarkers include body weight, body mass index (BMI), waist / hip ratio (WHR), plasma adipokines, and combinations of two or more thereof.

In certain embodiments, the compound used by one or more of the above methods is a compound of the formula I, Ia, Ib, Ic, Id, Ie, If, Ig or II, It is one of the specific compounds.

The compounds of the present invention may be administered to patients (animals and humans) in need of such treatment at dosages which will provide optimal pharmaceutical efficacy. The dosage required for use in any particular application will depend not only on the particular compound or composition selected but also on the route of administration, the nature of the condition being treated, the age and condition of the patient, the concurrent medication being administered by the patient, Will vary from patient to patient, diet, and other factors to be appreciated by those skilled in the art, and ultimately the appropriate dosage will be at the discretion of the attending physician. To treat the clinical conditions and diseases noted above, the compounds of the present invention may be formulated for oral, subcutaneous, topical, parenteral , By inhalation spray, or rectally. Parenteral administration may include subcutaneous injection, intravenous or intramuscular injection or infusion techniques.

The treatment can be continued for a long period or a short period as needed. The composition may be administered, for example, one to four times per day or more. The appropriate treatment period may be, for example, at least about one week, at least about two weeks, at least about one month, at least about six months, at least about one year, or at least one. The treatment period may be terminated if desired, e. G., When the weight loss goal is achieved. Therapeutic regimens may include a calibration period, a period during which a dose sufficient to reduce body weight is administered, for example, followed by a maintenance period during which an excess dose sufficient to increase body weight is administered. Suitable retention doses are likely to be found at the lower end of the dosage range provided herein, but accurate retention doses can be readily established for the individual subject by those skilled in the art without undue experimentation based on the description herein. Retention capacity can be used to maintain the body weight of a patient that has already been weight-adjusted by other means, including diet and exercise, obesity treatment such as bypass surgery or resection, or treatment with other pharmacological agents.

III. Pharmaceutical compositions and kits

Another aspect of the present invention provides a pharmaceutical composition comprising a compound as disclosed herein together with a pharmaceutically acceptable carrier. In particular, the present invention provides pharmaceutical compositions comprising the compounds described herein (i.e., formulated) together with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral or rectal, topical, oral, parenteral (e.g., subcutaneous, intramuscular, intradermal or intravenous), rectal, vaginal or aerosol administration, The most appropriate dosage form will depend on the severity and severity of the disease being treated and the nature of the particular compound employed. For example, the compositions of the present invention may be formulated in unit dosage form and / or may be formulated for oral or subcutaneous injection.

Exemplary pharmaceutical compositions of the invention may be formulated as pharmaceutical preparations in a mixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral use, for example, as one or more of the compounds of the present invention as an active ingredient Or in the form of a solid, semi-solid, or liquid containing the compound. The active ingredient may be formulated with conventional non-toxic pharmaceutically acceptable carriers for forms suitable, for example, as tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions and other applications. The active compound of interest is contained in the pharmaceutical composition in an amount sufficient to achieve the desired effect depending on the process or condition of the disease.

In order to prepare a solid composition such as a tablet, the main active ingredient is mixed with a pharmaceutical carrier such as conventional tablet ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, Calcium or gum and other pharmaceutical diluents such as water to form a pre-formulation composition of the solid containing a homogeneous mixture of the compound of the present invention, or a non-toxic pharmaceutically acceptable salt thereof . If these pre-formulation compositions are homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition such that the composition is easily further divided into equally effective unit dosage forms such as tablets, pills, capsules and the like.

In solid dosage forms (capsules, tablets, pills, dragees, powders, granules, etc.) for oral administration, the compositions of the present invention may contain one or more pharmaceutically acceptable carriers, for example sodium citrate or calcium phosphate , And / or is mixed with any one of the following: (1) a filler or diluent such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or acacia; (3) wetting agents, such as glycerol; (4) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, specific silicates and sodium carbonate; (5) solution retarders, for example paraffin; (6) absorption promoters, such as quaternary ammonium compounds; (7) wetting agents such as acetyl alcohol and glycerol monostearate; (8) absorbents such as kaolin and bentonite clay; (9) Lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; And (10) a colorant. In the case of capsules, tablets and pills, the compositions may also contain buffering agents. Solid compositions of a similar type may be used as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or lactose as well as high molecular weight polyethylene glycols and the like.

Tablets may optionally be prepared by compression or molding with one or more accessory ingredients. Compressed tablets may be prepared using binders (such as gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (such as sodium starch glycolate or crosslinked sodium carboxymethylcellulose), surface-active or dispersing agents . Molded tablets may be prepared by molding a mixture of the composition of the present invention moistened with an inert liquid diluent into a suitable machine. Tablets, and other solid dosage forms, such as dragees, capsules, pills, and granules, may be prepared by conventional means known in the art, for example, by means of coatings and shells, for example by enteric coatings well known in the pharmaceutical- Or may be fabricated.

Compositions for inhalation or insufflation include solutions and suspensions of pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the compositions of the present invention, the liquid dosage forms may be formulated with inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, (Especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, glycerol, sorbitol, Serine, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, cyclodextrin, and mixtures thereof.

The suspension may contain, in addition to the composition of the present invention, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar- , And mixtures thereof.

Formulations for rectal and vaginal administration may be prepared by mixing the compositions of the present invention with one or more suitable unstiffening excipients or carriers including, for example, cocoa butter, polyethylene glycol, suppository wax or salicylate Can be reconstituted as a suppository, which is solid at room temperature, but becomes liquid at body temperature, so that it dissolves in the body cavity and releases the active agent.

Dosage forms for transdermal administration of the compositions of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active ingredient, under sterile conditions, may be mixed with a pharmaceutically acceptable carrier, and any preservatives, buffers or propellants that may be required.

The ointments, pastes, creams and gels may contain, in addition to the composition of the present invention, animal or vegetable fats, oils, waxes, paraffins, starch, tracker cans, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, And mixtures thereof.

Powders and sprays may contain, in addition to the composition of the present invention, lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these materials. Sprays may additionally contain conventional propellants such as chlorofluorohydrocarbon and volatile unsubstituted hydrocarbons such as butane and propane.

The compositions and compounds of the present invention may alternatively be administered by an aerosol. This is done by preparing aqueous aerosols, liposome formulations or solid particles containing the compound. Non-aqueous (e. G., Fluorocarbon propellant) suspensions may be used. Sonic atomizers can be used because they minimize the exposure of the formulation to shear and thus can decompose the compounds contained in the compositions of the present invention. Usually an aqueous aerosol is prepared by combining an aqueous solution or suspension of the composition of the present invention together with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers will vary with the requirements of the particular composition of the invention but will typically include non-ionic surfactants (Tweens, Pluronics or polyethylene glycol), non-toxic proteins such as serum albumin, Esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

The pharmaceutical compositions of the present invention suitable for parenteral administration may be reconstituted into one or more pharmaceutically-acceptable sterile isotonic aqueous and non-aqueous solutions, dispersions, suspensions or emulsions, or sterile injectable solutions or dispersions just prior to use And sterile powders which may contain a solute, a bacterial growth inhibitor, a buffer, an antioxidant, which allows the formulation to be isotonic with the blood of a receptor or a suspending or thickening agent.

Examples of suitable aqueous and nonaqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable Oils, such as olive oil and injectable organic esters, such as ethyl oleate and cyclodextrin. Proper fluidity can be maintained, for example, by using a coating material such as lecithin, by maintaining the required particle size in the case of dispersion, and by using a surfactant.

In another aspect, disclosed compounds as enteric agents; And a pharmaceutically acceptable carrier or excipient thereof. Enteric material means a polymer that is substantially insoluble in the acidic environment above and is preferentially soluble in intestinal fluid at a particular pH. The small intestine is a part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenum, the plant and the chair. The pH of the duodenum is about 5.5, the pH of the plant is about 6.5, and the pH of the terminal ileum is about 7.5. Thus, the enteric material may be administered orally or parenterally, for example, about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, about 6.4, about 6.6, about 6.8, about 7.0, about 7.2, about 7.4, 7.6, about 7.8, about 8.0, about 8.2, about 8.4, about 8.6, about 8.8, about 9.0, about 9.2, about 9.4, about 9.6, about 9.8 or about 10.0. Exemplary enteric materials include but are not limited to cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, Hydroxypropylmethylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, aerials of methyl methacrylate and methyl methacrylate Copolymers of methyl acrylate and methyl methacrylate and methacrylic acid, copolymers of methyl vinyl ether and maleic anhydride (Gantrez ES series), ethyl methyl acrylate-methyl methacrylate (Such as Eudragit L30D55, Eudragit L30D55, Eudragit L30D55, Eudragit L30D55, Eudragit L30D55, and Eudragit L30D55 available from various commercial sources), natural resins such as polyvinylpyrrolidone, Durajite FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric and Aquateric). The solubility of these substances is respectively known or readily detectable in vitro. While the above is a list of possible materials, one of ordinary skill in the art will recognize that there are other enteric materials that are not inclusive and meet the objectives of the present invention, with the advantages disclosed.

Advantageously, a kit is provided for use by a consumer in need of weight loss, for example. Such kits include appropriate dosage forms such as those described above, and instructions describing how to use the dosage forms to adjust, reduce or prevent inflammation. The instructions will direct the consumer or medical practitioner to the dosage form according to the method of administration known to those skilled in the art. These kits could be advantageously packaged and sold in single or multiple kit units. An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packs generally consist of a sheet of relatively hard material, preferably covered with foil of a clear plastic material. During the packaging process, recesses are formed in the plastic foil. The recesses have the size and shape of the tablet or capsule to be packaged. The tablets or capsules are then placed in the recesses and a sheet of relatively rigid material is sealed against the plastic foil at the face of the foil opposite the direction in which the recesses are formed. As a result, the tablet or capsule is sealed in the concave portion between the plastic foil and the sheet. Preferably, the strength of the sheet is such that the pressure is manually applied on the recessed portions to allow the tablets or capsules to be removed from the blister pack by opening the inlet in the recessed sheet. Tablets or capsules can then be removed through the inlet.

It may be desirable to provide a memory aid on the kit in tabular form or capsule followed by a number so that the numbering of the prescribed tablets or capsules is taken to accommodate the number of days that the capsules should be ingested. Another example of such a memory aid is a calendar printed on a card, such as "First week, Monday, Tuesday, ... etc ... second week, Monday, Tuesday, .... & Other variants of the memory aid will be readily apparent. A "daily dose" may be a single tablet or capsule, or multiple pills or capsules, taken on a given day. In addition, the daily dose of the first compound may be comprised of one tablet or capsule, while the daily dose of the second compound may be comprised of several tablets or capsules, or vice versa. The memory aid should reflect this.

Also contemplated herein are methods and compositions comprising an administration step of a second active agent, or a second active agent. For example, in addition to being overweight or obese, the subject or patient may additionally have a disease or other adverse health condition that is exacerbated or promoted by an overweight-related or obesity-related accompanying disease, i.e., overweight or obesity . It is also contemplated herein that the disclosed compounds may be used in combination with at least one other agent that has already been found to treat such overweight-related and obesity-related disorders.

For example, type 2 diabetes is associated with obesity. Specific complications of type 2 diabetes such as disorders and diarrhea can be prevented, alleviated or eliminated by sustained weight loss (Astrup, A. Pub. Health Nutr (2001) 4: 499-515). Agents that are administered to treat type 2 diabetes include sulfonylureas (e.g., chlorpropha mide, glypizide, Glyburide, Glimepiride); Meglitinides (e.g., Repaglinide and Nateglinide); Biguanides (such as metformin); Thiazolinide ions (rosiglitazone, troglitazone and pioglitazone); Dipeptidylpeptidase-4 inhibitors (such as Sitagliptin, Vildagliptin, and Saxagliptin); Glucagon-like peptide-1 mimetics (e.g., Exenatide and Liraglutide); And alpha-glucosidase inhibitors (e.g., Acarbose and Miglitol).

Cardiac disorders and conditions such as hypertension, dyslipidemia, ischemic heart disease, cardiomyopathy, myocardial infarction, stroke, venous thromboembolic disease and pulmonary hypertension are associated with overweight or obesity. For example, hypertension is associated with obesity, because excessive fat tissue secretes substances acting on the kidneys to produce hypertension. Also, due to obesity, the amount of insulin produced (due to excessive fat tissue) is increasing, and this excess of insulin increases blood pressure. The main treatment option for hypertension is weight loss. Formulations administered to treat hypertension include Chlorthalidone; Hydrochlorothiazide; Indapamide, Metolazone; Loop diuretics (e.g., Bumetanide, Ethacrynic acid, Furosemide, Lasix, Torsemide); Potassium-preserving diuretics (e.g., Amiloride hydrochloride, benzamil, Spironolactone and Triamterene); A peripheral agent (e.g., Reserpine); Central alpha-agonists (e.g., Clonidine hydrochloride, guanabenzene acetic acid, guanfacine hydrochloride and Methyldopa); Alpha-blockers (e. G., Doxazosin mesylate, Prazosin hydrochloride and Terazosin hydrochloride; beta-blockers such as acebutolol Acebutolol, atenolol, betaxolol, bisoprolol fumarate, carteolol hydrochloride, metoprolol tartrate, metoprolol succinate, (Eg, Nadolol, Penbutolol sulfate, Pindolol, Propranolol hydrochloride and Timolol maleate), combined alpha and beta-blockers (eg, carvedilol (E.g., Carvedilol and Labetalol hydrochloride), direct vasodilators (e.g., Hydralazine hydrochloride and Minoxidil), calcium antagonists (e.g., Diltiazem hydrochloride such as amlodipine besylate, felodipine, isradipine, nicardipine, nifedipine, and the like, as well as dihydropyridines such as, for example, hydrochloride and verapamil hydrochloride; Nicolipril (Nisoldipine), ACE inhibitors (benazepril hydrochloride, Captopril, Enalapril maleate, Fosinopril sodium, Lisinopril, , Moexipril, Quinapril hydrochloride, Ramipril, Trandolapril); Angiotensin II receptor blockers (e.g., Losartan potassium, Valsartan and Irbesartan); Renin inhibitors (e. G., Aliskiren); And combinations thereof. These compounds are administered in dosages and dosages well known in the art.

Carr et al. (The Journal of Clinical Endocrinology & Metabolism (2004) Vol. 89, No. 6 2601-2607) discuss the link between overweight or obesity and dyslipidemia. Dyslipidemia is typically treated with statins. Statin, an HMG-CoA reductase inhibitor, slows down / slows the production of cholesterol in the subject or removes cholesterol accumulation in the arteries. Statins may be used in combination with mevastatin, lovastatin, pravastatin, simvastatin, velostatin, dihydrocompactin, fluvastatin, atorvastatin, , Dalvastatin, carvastatin, crilvastatin, bevastatin, cefvastatin, rosuvastatin, pitavastatin, and glenvastatin. (glenvastatin). These compounds are administered in dosages and dosages well known in the art. Eckel (Circulation (1997) 96: 3248-3250) discusses the relationship between overweight or obesity and ischemic heart disease. Agents that are administered to treat ischemic heart disease include statins, nitrates (e.g., isosorbide dinitrate and isosobaid mononitrate), beta-blockers, and calcium channel antagonists. These compounds are administered in dosages and dosages well known in the art.

Wong et al. (Nature Clinical Practice Cardiovascular Medicine (2007) 4: 436-443) discuss the relationship between overweight or obesity and cardiomyopathy. Formulations to be administered to treat cardiomyopathy include myocardial contractile stimulants such as digoxin, diuretics such as furosemide, ACE inhibitors, calcium antagonists, antiarrhythmic agents such as Sotolol, Amiodarone and Disopyramide, and beta-blockers. These compounds are administered in the form of pharmaceutical regimens and dosages known in the art. Yusef et al. (Lancet (2005) 366 (9497): 1640 -1649) discusses the relationship between overweight or obesity and myocardial infarction. Formulations administered to treat myocardial infarction include ACE inhibitors, angiogenesis II receptor blockers, direct vasodilators, beta blockers, antiarrhythmics and thrombolytics , Alteplase, Retaplase, Tenecteplase, Anistreplase and Urokinase). These compounds can be administered by any of the methods known in the art And dosage.

Suk et al. (Stroke (2003) 34: 1586-1592) discuss the relationship between overweight or obesity and stroke. Agents that are administered to treat a stroke include antiplatelet agents (e.g., aspirin, clopidogrel, dipyridamole and ticlopidine), anticoagulants (such as heparin), and thrombolytic agents. Stein et al. (The American Journal of Medicine (2005) 18 (9): 978-980) discuss the relationship between overweight or obesity and venous thromboembolic disease. Agents that are administered to treat venous thromboembolic diseases include antiplatelet agents, anticoagulants, and thrombolytic agents. Sztrymf et al. (Rev Pneumol Clin (2002) 58 (2): 104-10) discuss the relationship between overweight or obesity and pulmonary hypertension. (E.g., K-dur), vasodilators (e.g., Nifedipine and Diltiazem), Bosentan, and the like. In addition, agents that are administered to treat pulmonary hypertension include myocardial contraction stimulators, anticoagulants, diuretics, potassium , Epoprostenol and sildenafil. ≪ RTI ID = 0.0 > Respiratory disorders and conditions such as obesity-hypoventilation syndrome, asthma and obstructive sleep apnea are associated with overweight or obesity. Elamin ( Chest (2004) 125: 1972-1974) discusses the relationship between overweight or obesity and asthma. Agents administered to treat asthma include bronchodilators, anti-inflammatory agents, leukotriene blocking agents, and anti-Ige agents. Certain asthma medicines may be administered in combination with one or more of the following agents: Zafirlukast, Flunisolide, Triamcinolone, Beclomethasone, Terbutaline, Fluticasone, Formoterol Formoterol, Beclomethasone, Salmeterol, Theophylline, and Xopenex.

Kessler et al. (Eur Respir J (1996) 9: 787-794) discuss the relationship between overweight or obesity and obstructive sleep apnea. Formulations administered to treat sleep apnea include modafinil and amphetamine.

Liver disorders and conditions, for example, nonalcoholic fatty liver disease, are associated with overweight or obesity. Tolman et al. (Ther Clin Risk Manag (2007) 6: 1153-1163) discuss the relationship between overweight or obesity and nonalcoholic fatty liver disease. Formulations administered to treat nonalcoholic fatty liver disease include, but are not limited to, antioxidants (e.g., Vitamin E and C), insulin sensitizers (Metformin, Pioglitazone, Rosiglitazone and Betaine) Liver protectants and lipid-lowering agents.

Skeletal disorders and conditions such as back pain and weight-bearing joint osteoarthritis are associated with overweight or obesity. van Saase (J Rheumatol (1988) 15 (7): 1152-1158) discusses the relationship between overweight or obesity and weight-bearing joint osteoarthritis. Formulations administered to treat osteoarthritis of the weight-bearing joint include acetaminophen, non-steroidal anti-inflammatory agents such as ibuprofen, Etodolac, (Eg, oxaprozin, naproxen, diclofenac and nabumetone), COX-2 inhibitors (eg, Celecoxib), steroids, supplements (eg, glucosamine And chondroitin sulfate) and artificial joint fluids.

Metabolic disorders and conditions, such as, for example, Felder-Willie syndrome and polycystic ovarian syndrome, are associated with overweight or obesity. Cassidy (Journal of Medical Genetics (1997) 34: 917-923) discusses the relationship between overweight or obesity and the Frieder-Willie syndrome. Agents administered to treat Frieder-Willie syndrome include human growth hormone (HGH), somatropin and weight loss agents such as Orlistat, Sibutramine, Methamphetamine, Ionamin Ionamin, Phentermine, Bupropion, Diethylpropion, Phendimetrazine, Benzphetermine, and Topamax).

Hoeger (Obstetrics and Gynecology Clinics of North America (2001) 28 (1): 85-97) discusses the relationship between overweight or obesity and polycystic ovary syndrome. Formulations administered to treat polycystic ovary syndrome include insulin-sensitizing agents, a combination of synthetic estrogens and progesterone, Spironolactone, Eflornithine and Clomiphene. Reproductive disorders and conditions, such as sexual dysfunction, erectile dysfunction, infertility, obstetric complications and fetal abnormalities, are associated with overweight or obesity. Larsen et al. (Int J Obes (Lond) (2007) 8: 1189-1198) discuss the relationship between overweight or obesity and sexual dysfunction. Chung et al. (Eur Urol (1999) 36 (1): 68-70) discuss the relationship between overweight or obesity and erectile dysfunction. Agents that are administered to treat erectile dysfunction include, but are not limited to, phosphodiesterase inhibitors (e.g., Tadalafil, Sildenafil citrate and Vardenafil), prostaglandin E analogs Alprostadil), alkaloids (e.g., Yohimbine), and testosterone. Pasquali et al. (Hum Reprod (1997) 1: 82-87) discuss the relationship between overweight or obesity and infertility. Formulations administered to treat infertility include Clomiphene, Clomiphene citrate, Bromocriptine, Gonadotropin-Releasing Hormone (GnRH), GnRH agonists, GnRH (S), antagonist, tamoxifen / nolvadex, gonadotropin, human chorionic gonadotropin (HCG), menopausal gonadotropin (HmG), progesterone, (FSH), Urofollitropin, Heparin, Follitropin alfa, and Follitropin beta. In the present invention, the term "

Weiss et al. (American Journal of Obstetrics and Gynecology (2004) 190 (4): 1091-1097) discuss the relationship between overweight or obesity and obstetric complications. The formulations to be administered to treat obstetric complications include Bupivacaine hydrochloride, Dinoprostone PGE2, Meperidine HCl, Ferro-folic-500 / (iberet-folic) -500, Meperidine, Methylergonovine maleate, Ropivacaine HCl, Nalbuphine HCl, Oxymorphone HCl, Oxytocin Oxytocin, Dinoprostone, Ritodrine, Scopolamine Hydrobromide, Sufentanil Citrate, and Oxytocic.

Psychiatric disorders and conditions, such as weight-related depression and anxiety, are associated with overweight or obesity. Dixson et al. (Arch Intern Med (2003) 163: 2058-2065) discuss the relationship between overweight or obesity and depression. Agents that are administered to treat depression include serotonin reuptake inhibitors (e.g., fluoxetine, escitalopram, citalopram, paroxetine, sertraline, Venlafaxine); A tricyclic antidepressant such as amitriptyline, amoxapine, clomipramine, desipramine, doculepin hydrochloride, doxepin, imipraine, Imipramine, Iprindole, Lofepramine, Nortriptyline, Opipramol, Protriptyline, and Trimipramine); Monoamine oxidase inhibitors (such as isocarboxazid, Moclobemide, Phenelzine, Tranylcypromine, Selegiline, Rasagiline, , Nialamide, Iproniazid, Iproclozide, Toloxatone, Linezolid, Dienolide kavapyrone desmethoxyyangonin, ) And dextroamphetamine); Psychostimulants (e.g., Amphetamine, Methamphetamine, Methylphenidate and Arecoline); But are not limited to, antipsychotic drugs such as butyrophenones, phenothiazines, thioxanthenes, clozapine, olanzapine, risperidone, quetiapine, Ziprasidone, Amisulpride, Paliperidone, Symbyax, Tetrabenazine, and Cannabidiol); And mood stabilizers such as lithium carbonate, valproic acid, Divalproex sodium, sodium valproate, Lamotrigine, Carbamazepine, Gabapentin, Oxcarbazepine, ) And topiramate).

Simon et al. (Archives of General Psychiatry (2006) 63 (7): 824-830) discuss the relationship between overweight or obesity and anxiety. Formulations to be administered to treat anxiety include serotonin reuptake inhibitors, mood stabilizers, benzodiazepines (e.g., Alprazolam, Clonazepam, Diazepam and Lorazepam), tricyclic antidepressants, Monoamine oxidase inhibitors and beta-blockers.

Another aspect of the present invention provides a method of facilitating and maintaining weight loss in a subject comprising administering to the subject an amount of the disclosed compound effective to cause weight loss in the subject; And administering a therapeutically effective amount of another weight loss to maintain a reduced body weight of the subject. Weight loss agents include serotonin and noradrenaline reuptake inhibitors; Noradrenaline reuptake inhibitors; Selective serotonin reuptake inhibitors; And intestinal lipase inhibitors. Certain weight loss formulations include orlistat, sibutramine, methamphetamine, ionamine, phentermine, bupropion, diethylpropion, fendimetrazine, (DGAT1) activity by blocking the action of pancreatin, phendimetrazine, benzphetermine, bromocriptine, lorcaserin, topiramate, or ghrelin, or inhibiting the activity of diacylglycerol acyltransferase 1 , Inhibit the activity of stearoyl CoA unsaturated enzyme 1 (SCD1), inhibit neuropeptide Y receptor 1 function, activate neuropeptide Y receptor 2 or 4 function, or activate sodium neurotransmitter 1 or 2 < / RTI > These compounds are administered in dosages and dosages well known in the art.

Example

The compounds disclosed herein may be prepared in a variety of ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the following synthesis methods, unless otherwise indicated, all proposed reaction conditions, including solvent, reaction atmosphere, reaction temperature, experimental duration and workup procedures, can be selected to be the conditional standard for the reaction It should be understood. It is understood by those skilled in the art of organic synthesis that functional groups present on various parts of the molecule should be compatible with the proposed reagents and reactions. Substituents that are incompatible with the reaction conditions will be apparent to those skilled in the art and therefore alternative methods are indicated. The starting materials for the examples are either commercially available or readily prepared by standard methods from known materials.

At least some of the compounds identified herein as "intermediate products" are assumed to be the compounds of the present invention.

1 H NMR spectra can be obtained, for example, using a Varian Unity Inova (400 MHz) spectrometer with a triple resonant 5 mm probe for the example compounds, and Bruker Abras Was recorded at ambient temperature using a Bruker Avance DRX (400 MHz) spectrometer or a Bruker Abans DPX (300 MHz) spectrometer. Chemical shifts are expressed in ppm relative to tetramethylsilane. The following abbreviations are used: br = Broad signal, s = singlet, d = doublet, dd = double doublet, dt = double triplet, ddd = double double, t = triple, , tdd = triple doublet, q = quadruplet, m = multiplet.

Mass spectroscopy (LCMS) experiments for measuring residence time and associated mass ions were performed using the following methods:

Method A: The experiment was performed on a Waters ZMD LC quadrupole mass spectrometer connected to a Hewlett Packard HP1100 LC system equipped with a diode array detector. The spectrometer has an electrospray source operating in positive and negative ion modes. LC was performed using a Luna 3 micron 30 x 4.6 mm C18 column and a 2 ml / min flow rate. The initial solvent system consisted of 95% (solvent A) of water containing 0.1% formic acid and 5% (solvent B) of acetonitrile containing 0.1% formic acid for the first 0.5 minutes, followed by solvent A 5% And solvent B up to 95%. The final solvent system was kept constant for a further 1 minute.

Method B: The experiment was performed on a Waters Micromass ZQ2000 quadrupole mass spectrometer coupled to a Waters Acquity UPLC system equipped with a PDA UV detector. The spectrometer has an electrospray source operating in positive and negative ion modes. The LC was performed using an archaic BEH 1.7 micron C18 column, an arithmetic tee BEH Shield RP18 column, or an arcata HSST 1.8 micron column. Each column had dimensions of 100 x 2.1 mm and was maintained at 40 캜 at a flow rate of 0.4 ml / min. The initial solvent system was 95% water (solvent A) containing 0.1% formic acid for the first 0.4 minutes and 5% acetonitrile (solvent B) containing 0.1% formic acid followed by solvent A 5% over the next 6 minutes. And solvent B up to 95%. The final solvent system was kept constant for a further 0.8 minutes.

Microwave experiments were performed using a Biotage Initiator (TM), which uses a single-mode resonator and dynamic field tuning, both of which provide regeneration and control. A temperature of 40 to 250 DEG C can be achieved and a pressure of less than 20 bar can be reached. The installation exists to apply air cooling during the irradiation.

Partial HPLC purification was performed on a Genesis C18-reversed-phase column (C18) or a Phenomenex made C6-phenyl column (C6-phenyl) (100 x 22.5 mm ID, particle size 7 microns at 230 or 254 nm Elution with a gradient of 100-0 to 0-100% water / acetonitrile containing 0.1% formic acid or water / methanol using UV detection, flow rate 5-15 ml / min. The fractions containing the required product (identified by LCMS analysis) were pooled, the organic fraction was removed by evaporation and the remaining aqueous fraction was freeze-dried to give the product.

Compounds that require column chromatography may be either a Biotage SP1 (TM) Flash Purification system with Touch Logic Control (TM), or a pre-packed silica gel Combiflash Companion (registered trademark) with silica gel SPL, Silica gel, Isolute SPE cartridge, Biotage SNAP cartridge or Redisep Rf cartridge, ≪ / RTI > trademark).

The compounds were named using Autonom 2000 from ISISDraw.

Abbreviation:

DCM dichloromethane

DMF N, N-dimethylformamide

DMAP 4-dimethylaminopyridine

THF tetrahydrofuran

DMSO dimethylsulfoxide

TFA Trifluoroacetic acid

DMAW-60 DCM / methanol / acetic acid / water 60: 18: 3: 2

DMAW-120 DCM / methanol / acetic acid / water 120: 15: 3: 2

Example 1: Preparation of (R) -7- [2 - ((Z) -3- diethylaminoprop-1-enyl) -4-fluorobenzenesulfonyl- amino] -2,3,3a, 4- Tetrahydro-1H-benzo [b] pyrrolo [1,2-d] [1,4] oxazine-6-

Figure pct00012

To a stirred solution of < RTI ID = 0.0 > methyl (l, (R) -7- [2 - ((Z) -3-diethylaminoprop-1-enyl) -4-fluorobenzene- sulfonylamino] -2,3,3a, 4- tetrahydro-1H (Intermediate 1, 0.640 g) and lithium hydroxide monohydrate (0.505 g) was treated with 135 < RTI ID = 0.0 >Lt; 0 > C. The mixture was acidified with formic acid, diluted with ethanol and toluene and then concentrated in vacuo. The residue was triturated with methanol in DCM (10% solution) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica eluting with a gradient of 0-10% using a mixture of methanol and DCM. The resulting solid was triturated with ethyl acetate to give a pale yellow solid which was treated with hot ethyl acetate and still filtered under hot conditions. The filtrate was concentrated in vacuo and the residue was triturated with ethyl acetate to give (R) -7- [2- ((Z) -3- diethylaminoprop-1-en- L, 2-d] [1,4] oxazine-6-carboxylic acid (0.299 g, ) As a pale yellow solid.

1 H NMR (CDCl 3) δ : 7.71 (1H, d), 7.39 (1H, dd), 7.14 (1H, d), 6.86 (1H, td), 6.76 (1H, dd), 6.51 (1H, d) (2H, m), 5.93 (1H, td), 4.41 (1H, dd), 4.15 (1H, br, s), 3.56-3.45 , 1.39-1.37 (1H, m), 1.28 (6H, m).

LCMS (Method B) r / t 3.28 (M + H) <

Example 2: (S) -7- [2 - ((Z) -3-Diethylaminoprop-1-enyl) -4-fluorobenzenesulfonyl-amino] -2,3,3a, 4- Tetrahydro-1H-benzo [b] pyrrolo [1,2-d] [1,4] oxazine-6-

Figure pct00013

methyl (S) -7- [2 - ((Z) -3-diethylaminoprop-1-enyl) -4-fluorobenzenesulfonylamino] -2,3,3a, 4- tetrahydro- Benzo [b] pyrrolo [1,2-d] [1,4] oxazine-6-carboxylate (Intermediate 11).

1 H NMR (CDCl 3) δ : 7.71 (1H, d), 7.39 (1H, dd), 7.13 (1H, d), 6.86 (1H, td), 6.76 (1H, dd), 6.51 (1H, d) (1H, m), 5.93 (1H, ddd), 4.40 (1H, dd), 4.16 (1H, br, s), 3.56-3.44 (3H, m), 3.31-3.08 , 1.44-1.32 (1 H, m), 1.28 (6 H, t).

LCMS (method B) r / t 3.29 (M + H) <

Example 3: 7- [2 - ((Z) -3-Diethylaminoprop-1-enyl) -4-fluorobenzenesulfonylamino] -2,3-dihydro-lH- pyrrolo [ , 2-a] indole-8-carboxylic acid

Figure pct00014

To a solution of methyl 7- [2 - ((Z) -3-diethylaminoprop-1-enyl) -4-fluorobenzenesulfonylamino] -2,3- A suspension of dihydro-lH-pyrrolo [1,2-a] indole-8-carboxylate (intermediate 16, 0.092 g) and lithium hydroxide monohydrate (0.077 g) was microwave irradiated at 135 & . After cooling, the mixture was acidified to pH 4 with formic acid. Ethanol and toluene were added and the resulting mixture was concentrated in vacuo. The residue was triturated with methanol in DCM (10% solution) and the resulting solid was filtered off and washed with DCM. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica eluting with a gradient of 0 to 8% using a mixture of methanol and DCM. The resulting solid was triturated with ethyl acetate and dried in vacuo at 60 < 0 > C overnight to give 7- [2- ((Z) -3-diethylaminoprop- 1-enyl) -4-fluorobenzenesulfonylamino ] -2,3-dihydro-lH-pyrrolo [l, 2-a] indole-8-carboxylic acid (0.039 g) as a light yellow solid.

1 H NMR (CDCl 3) δ : 7.68 (1H, d), 7.54 (1H, br, s), 7.41 (1H, d), 7.18 (1H, d), 6.80 (1H, br, t), 6.74 ( (1H, dd), 6.67 (1H, s), 6.07 (1H, m), 4.02 (2H, t), 3.70 , 2.57 (2H, m), 1.27 (6H, t).

LCMS (Method B) r / t 3.42 (M + H) 486

Example 4: 7-Benzenesulfonylamino-2,3-dihydro-lH-pyrrolo [1,2-a] indole-8-

Figure pct00015

To a solution of methyl 7-benzenesulfonylamino-2,3-dihydro-lH-pyrrolo [1,2-a] indole-8-carboxylate (intermediate 26, 0.075 g) and lithium hydroxide monohydrate (0.049 g) was irradiated with microwave at 110 캜 for 20 minutes. After cooling, the mixture was diluted with water and acidified to pH 4 to 5 with formic acid. The resulting solid was washed with water and ether and then dried to give a cream-colored powder. This solid was dissolved in methanol and acetone, lyophilized, and then dried in a desiccator at 40 占 폚 in a vacuum overnight. The resulting solid was triturated with DCM, filtered, washed with DCM (1 mL) and pentane (1 mL) and then dried overnight in a desiccator at 40 < 0 > C in vacuo. The yellow solid was dissolved in hot ethyl acetate and pentane was added until the mixture became turbid. Upon cooling, the resulting solid was collected by filtration, washed with pentane and dried overnight in a desiccator at 40 < 0 > C in vacuo to give 7-benzenesulfonylamino-2,3-dihydro-lH-pyrrolo [ 1,2-a] indole (0.023 g) as a cream colored solid.

1 H NMR (DMSO-d 6 ) ?: 7.66 (2H, m), 7.58-7.43 (4H, m), 7.29 2H, t), 2.53 (2H, m).

LCMS (method B) r / t 4.41 (M + H) 357

Example 5: 7- [2 - ((Z) -3-Diethylaminoprop-1-enyl) -4-fluorobenzenesulfonylamino] -2,3,9,9a-tetrahydro- Pyrrolo [l, 2-a] indole-8-carboxylic acid

Figure pct00016

To a solution of methyl 7- [2 - ((Z) -3-diethylaminoprop-1-enyl) -4-fluorobenzenesulfonylamino] -2,3, (Intermediate 27, 0.311 g) and lithium hydroxide monohydrate (0.526 g) was stirred at 135 < 0 > C for 45 min And irradiated with microwave. After cooling, the mixture was diluted with methanol and acidified with formic acid. The mixture was concentrated in vacuo, the residue was diluted with ethanol and toluene and again concentrated in vacuo. The residue was triturated with methanol in DCM (20% solution). The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica eluting with a gradient of 0 to 20% using a mixture of methanol and DCM. The resulting solid was triturated with ethyl acetate to give a light yellow solid which was purified by preparative HPLC (C18) eluting with a gradient of 5-70% using a mixture of acetonitrile and water containing 0.1% formic acid, Amino] -2,3,9,9a-tetrahydro-lH-pyrrolo [2,3-d] pyrimidin-4- 1,2-a] indole-8-carboxylic acid (0.090 g).

1 H NMR (CDCl 3 )?: 7.69 (1H, d), 7.38 (2H, m), 6.84 , 3.88 (2H, m), 3.56 (1H, br s), 3.40-3.04 (9H, m), 1.80 (3H, m), 1.28 (6H, t).

LCMS (Method B) r / t 2.40 (M + H) 488

Examples 6 and 7: Isolation of Enantiomers from Example 5

Chiral separation was performed using a Chiralpak IC column (10 mm x 250 mm, particle size 5 micron) eluting with anhydrous ethanol for the sample from Example 5. Each separated enantiomer was purified by preparative HPLC (C18) eluting with a gradient of 5-98% using a mixture of acetonitrile and water containing 0.1% ammonia.

Example 6: Retention time on first eluting enantiomer, chiral column, 23 min.

1 H NMR (CD 3 OD)?: 7.68 (1H, m), 7.54 (1H, d), 7.33 ), 3.91-3.77 (3H, m), 3.35 (1H, m), 3.27-3.09 (8H, m), 1.92-1.77 (3H, m), 1.26 (6H, t).

LCMS (Method B) r / t 2.48 (M + H) 488

Example 7: Second eluting enantiomer, residence time on chiral column 35 min

1 H NMR (CD 3 OD)?: 7.68 (1H, m), 7.55 (1H, d), 7.33 m), 3.94-3.79 (3H, m), 3.35 (1H m), 3.28-3.11 (8H, m), 1.93-1.75 (3H, m), 1.26 (6H, t).

LCMS (Method B) r / t 2.50 (M + H) 488

Example 8: 7- [2 - ((Z) -3-Diethylaminoprop-1-enyl) -4-fluorobenzenesulfonylamino] -1,2,3,3a, 4,5- Hydroxypyrrolo [1,2-a] quinoline-6-carboxylic acid

Figure pct00017

To a solution of methyl 7- [2- ((Z) -3-diethylaminoprop-1-enyl) -4-fluorobenzenesulfonylamino] -1,2,3,4- A mixture of 3,3a, 4,5-hexahydropyrrolo [1,2-a] quinoline-6-carboxylate (intermediate 31, 0.48g) and lithium hydroxide monohydrate (0.526g) Gt; min. ≪ / RTI > After cooling, the mixture was diluted with methanol, acidified with formic acid and then evaporated in vacuo. The residue was triturated with 10% methanol in DCM and filtered. The filtrate was evaporated in vacuo and purified by chromatography on silica eluting with a gradient of 0-15% using a mixture of methanol and DCM. The resulting solid was triturated with acetone and filtered to give 7- [2 - ((Z) -3- diethylaminoprop-1-enyl) -4-fluorobenzenesulfonylamino] 3a, 4,5-hexahydro-pyrrolo [l, 2-a] quinoline-6-carboxylic acid (0.14 g) as a pale yellow solid.

1 H NMR (DMSO-d 6 ) δ: 7.40 (2H, m), 7.19 (2H, m), 7.05 (1H, d), 6.29 (1H, d), 6.18 (1H, m), 3.93 (1H, br, t), 3.69 (1H, br, dd), 3.40-3.00 (8H, m), 2.75 1H, m), 1.18 (6H, t), 1.06 (1H, m).

LCMS (Method B) r / t 3.50 (M + H) 502.

Example 9: (R) -6- [2 - ((Z) -3-Diethylaminoprop-1-enyl) -4-fluorobenzenesulfonylamino] -1,2,2a, 3- Hydroxy-4-oxa-8b-azacyclobuta [a] naphthalene-5-carboxylic acid

Figure pct00018

To a solution of tert -butyl (R) -6- [2- ((Z) -3-diethylaminoprop-1-enyl) -4-fluorobenzenesulfonyl- (A) naphthalene-5-carboxylate (intermediate 42, 0.017 g) was allowed to stand at room temperature for 30 min and the solution was allowed to warm to ambient temperature It was then concentrated in vacuo. The residue was dissolved in methanol (15 ml), potassium carbonate (0.2 g) was added and the mixture was stirred for 5 minutes and then filtered. The filtrate was acidified with formic acid and concentrated in vacuo. The residue was triturated with 20% methanol in DCM and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica eluting with a gradient of 0 to 20% using a mixture of methanol and DCM. The resulting solid was triturated with diethyl ether and filtered to give (R) -6- [2 - ((Z) -3-diethylaminoprop-1-enyl) -4-fluorobenzenesulfonylamino] Aza-naphthalene-5-carboxylic acid (0.008 g) as a pale brown solid.

1 H NMR (CDCl 3) δ : 9.2-9.8, (1H, br, s), 7.69 (1H, d), 7.36 (1H, dd), 7.16 (1H, d), 6.84 (1H, dt), 6.75 (1H, d), 6.61 (1H, d), 5.92 (1H, m), 4.33 (1H, m), 4.24-4.12 (1H, m), 3.28 (2H, m), 3.14 (2H, m), 2.69 (1H, m), 1.98 (1H,

LCMS (Method B) r / t 2.80 (M + H) 490.

Example 10: 6- [2 - ((Z) -3-Diethylaminoprop-1-enyl) -4-fluorobenzenesulfonylamino] -2,3-dihydro-1H- benzo [d] Pyrrolo [l, 2-a] imidazole-5-carboxylic acid

Figure pct00019

To a solution of methyl 6- [2 - ((Z) -3-diethylaminoprop-1-enyl) -4-fluorobenzenesulfonylamino] -2,3- A mixture of dihydro-1H- benzo [d] pyrrolo [1,2-a] imidazole-5-carboxylate (intermediate 53, 0.16 g) and lithium hydroxide monohydrate (0.526 g) Lt; / RTI > After cooling, the mixture was diluted with methanol, acidified with formic acid and then evaporated in vacuo. The residue was azeotroped with a mixture of toluene and ethanol and the residue was triturated with 20% methanol in DCM and then filtered. The filtrate was evaporated in vacuo and the residue was purified by chromatography on silica eluting with DMAW-60. The resulting solid was further purified by HPLC (C18) to give 6- [2- ((Z) -3-diethylaminoprop-1-enyl) -4-fluorobenzenesulfonylamino] LH-benzo [d] pyrrolo [l, 2-a] imidazole-5-carboxylic acid (0.035 g).

1 H NMR (DMSO-d 6 )?: 7.82 (1H, dd), 7.46 (1H, d), 7.30 t), 3.36 (2H, d), 3.03 (2H, t), 2.55-2.74 (6H, m), 0.94 (6H, t).

LCMS (Method B) r / t 2.54 (M + H) 487.

Intermediate 1: methyl (R) -7- [2 - ((Z) -3-diethylaminoprop-1-enyl) -4-fluorobenzenesulfonylamino] -2,3,3a, 4-tetrahydro- Benzo [b] pyrrolo [1,2-d] [1,4] oxazine-6-carboxylate

Figure pct00020

To a solution of < RTI ID = 0.0 > methyl < (R) -7- (2-bromo-4-fluorobenzenesulfonylamino) -2,3,3a, 4-tetrahydro-1H- benzo [b] pyrrolo [ 3-yl), 4] oxazine-6-carboxylate (intermediate product 2, 0.606 g) and N, N - diethyl- -butyl phosphonium tetrafluoroborate -amine degassed solution of (intermediate 3, 1.01g) and, after purged with nitrogen, tris (dibenzylideneacetone) dipalladium (0) (0.057g) and tri-tert borate (0.036g) were added. the reaction mixture was heated at 95 ℃ for 1 hour under nitrogen atmosphere. the mixture was cooled, then diluted with ethyl acetate, after washing with water and drying (Na 2 SO 4) The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica eluting with a gradient of 0 to 10% using a mixture of methanol and DCM to give methyl (R) -7- [2 - ((Z) -3-diethylaminoprop-1-enyl) -4-fluorobenzenesulfonylamino] -2,3,3a, 4-tetrahydro- Benzo [b] pyrrolo [1,2-d] [1,4] oxazine-6-carboxylate (0.660 g) as a yellow foam.

1 H NMR (CDCl 3) δ : 7.89 (1H, dd), 7.02 (2H, m), 6.89 (1H, d), 6.77 (1H, d), 6.52 (1H, d), 6.02 (1H, m) M), 2.65 (4H, br s), 2.15-1.91 (3H, m), 3.45-3.43 (2H, m) , 1.47-1.26 (1H, m), 1.04 (6H, br, t).

Intermediate 2: methyl (R) -7- (2-bromo-4-fluorobenzenesulfonylamino) -2,3,3a, 4-tetrahydro-1H- benzo [b] pyrrolo [ , 4] oxazine-6-carboxylate

Figure pct00021

2-Bromo-4-fluorobenzenesulfonyl chloride (0.656 g) was dissolved in pyridine (10 ml) and DCM (10 ml) (R) -7-amino-2,3,3a, 4-tetrahydro- lH-benzo [b] pyrrolo [ , 0.525 g) in dichloromethane (5 ml) and the mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and 0.5 M hydrochloric acid solution. The organic layer was dried (Na 2 SO 4), then filtered, and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica eluting with a gradient of 0-40% using a mixture of ethyl acetate and cyclohexane to give a light yellow solid which was triturated with ether and cyclohexane (1: 2) methyl (R) -7- (2-bromo-4-fluorobenzenesulfonylamino) -2,3,3a, 4-tetrahydro-1H- benzo [b] pyrrolo [ , 4] oxazine-6-carboxylate (0.820 g).

1 H NMR (CDCl 3) δ : 8.28 (1H, br, s), 7.96 (1H, dd), 7.40 (1H, dd), 7.06-6.99 (2H, m), 6.49 (1H, d), 4.43 ( (1H, dd), 3.85 (3H, s), 3.53 (1H, tdd), 3.45 (1H, td), 3.26 -1.90 (1H, m), 1.45-1.33 (1H, m).

Intermediate 3: N, N-diethyl -N - ((Z) -1-tributylamine Stan nanil prop-1-en-3-yl) -amine

Figure pct00022

Diethylamine (19 ml) was added to a solution of ((Z) -3-bromoprop-1-enyl) -tributyl-stannane (Intermediate 4, 7.52 g) in THF The mixture was stirred for 3 hours. The reaction mixture was evaporated to dryness and the residue was purified by chromatography on a silica column pre-washed with 20% triethylamine in acetonitrile. The column was eluted with a gradient of 0-10% using a mixture of ethyl acetate and pentane to give N, N-diethyl-N- ((Z) -1-tributylstannanylprop- -Yl) -amine (4.75 g) as an orange oil.

1 H NMR (CDCl 3) δ : 6.59 (1H, dt), 5.97 (1H, dt), 3.08 (2H, dd), 2.53 (4H, q), 1.49 (6H, m), 1.37-1.24 (6H, m), 1.04 (6H, t), 0.92-0.89 (15H, m).

Intermediate 4: ((Z) -3-bromopropyl-1-enyl) -tributylstannane

Figure pct00023

A solution of triphenylphosphine (5.32 g) in DCM (60 ml) was added to a solution of (Z) -3-tributylstannanylpropyl-2-en- ) And carbon tetrabromide (9.18 g) in dichloromethane (10 ml) and the mixture was stirred for 2.5 hours. The mixture was concentrated to low volume and pentane was added. The obtained solid was removed by filtration, and the filtrate was evaporated to dryness. Pentane was added and the resulting solid was again removed by filtration and the filtrate was evaporated to dryness to give ((Z) -3-bromopropyl-1-enyl) -tributylstannane (12.14 g) as an oil .

1 H NMR (CDCl 3 )?: 6.71 (1H, dt), 6.11 (1H, d), 3.88 (2H, d), 1.52-1.50 (6H, m), 1.37-1.27 0.97 (6 H, m), 0.90 (9 H, t).

Intermediate 5: (Z) -3-tributylstannanyl-prop-2-en-1-ol

Figure pct00024

Propargyl alcohol (5 mL) was added to a solution of lithium aluminum hydride (1M in THF, 43 mL) in THF (70 mL) at -78 <0> C. The resulting mixture was allowed to warm to room temperature and stirred for 18 hours. This was cooled to -78 ° C and a solution of tri-n-butyltin chloride (8.32 ml) in diethyl ether (50 ml) was added and the mixture was stirred for 3 hours while gradually warming to room temperature. The reaction mixture was cooled to -5 [deg.] C and quenched by addition of water and a 15% aqueous sodium hydroxide solution, then allowed to warm to room temperature. Ethyl acetate was added and the mixture was stirred for 1 hour. The precipitate was filtered through Celite and the filtrate was evaporated to dryness. The residue was purified by chromatography on a silica column pre-washed with 20% triethylamine in acetonitrile. The column was eluted with a gradient of 0-10% using a mixture of ethyl acetate and pentane to give 5.06 g of (Z) -3-tributylstannanyl-prop-2-en-1-ol as a clear oil &Lt; / RTI &gt;

1 H NMR (CDCl 3) δ : 6.70 (1H, dt), 6.08 (1H, dt), 4.12 (2H, dd), 1.49 (6H, m), 1.31 (6H, m), 0.98-0.84 (15H, m).

Intermediate 6: Methyl (R) -7-amino-2,3,3a, 4-tetrahydro-1H-benzo [b] pyrrolo [

Figure pct00025

To a solution of methyl &lt; RTI ID = 0.0 &gt; ((R) -1-pyrrolidin-2-ylmethoxy) benzoate (intermediate 7, 1.65 g), palladium acetate (0.281 g), (+/-) -2,2'- bis (diphenylphosphino) -1,1'-binaphthalene (1.56 g) and cesium carbonate (3.26 g) was heated at 100 ° C under a nitrogen atmosphere for 2 hours. The mixture was cooled and partitioned between ethyl acetate and water. The organic layer was dried (Na 2 SO 4), then filtered, and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica eluting with a gradient of 0-40% using a mixture of ethyl acetate and cyclohexane to give methyl L, 2-d] [1,4] oxazine-6-carboxylate (0.528 g) was added to a solution of (R) -7-amino-2,3,3a, 4- tetrahydro- Lt; / RTI &gt; as a black oil.

LCMS (Method A) rt 2.09 (M + H) 249

Intermediate 7: Methyl 6-Amino-3-bromo-2 - ((R) -l-pyrrolidin-2-ylmethoxy) benzoate

Figure pct00026

TFA (20 mL) and tert -butyl &lt; RTI ID = 0.0 &gt; (R) -2- [6-bromo-3- bis- (tert -butoxycarbonyl) amino-2- methoxycarbonylphenoxymethyl] pyrrolidine- 1-carboxylate g) was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate and washed with aqueous potassium carbonate solution. The aqueous layer was extracted with ethyl acetate, dried (Na 2 SO 4 ) and then filtered. The filtrate was concentrated in vacuo to give methyl Amino-3-bromo-2 - ((R) -1-pyrrolidin-2-ylmethoxy) benzoate (1.65 g) as a colorless gum.

LCMS (Method A) r / t 2.12 (M + H) 329/331

Intermediate 8: tert -Butyl (R) -2- [6-bromo-3- bis- (tert -butoxycarbonyl) amino-2- methoxycarbonylphenoxymethyl] pyrrolidine-

Figure pct00027

Diisopropyl azodicarboxylate (1.21 g) was added to a solution of methyl 3-bromo-6- bis- (tert -butoxycarbonyl) amino-2-hydroxybenzoate (intermediate 9, Was added to a solution of tert -butyl (R) -2-hydroxymethylpyrrolidine-1-carboxylate (1.11 g) and triphenylphosphine (1.57 g) and the reaction mixture was stirred at room temperature After stirring for 30 minutes, it was allowed to stand overnight. The mixture was concentrated in vacuo and the residue was purified by chromatography on silica eluting with a gradient of 0-30% using a mixture of ethyl acetate and cyclohexane to give tert -butyl ( 3.17 g ) was added to a solution of (R) -2- [6-bromo-3- (tert -butoxycarbonyl) amino-2- methoxycarbonyl- phenoxymethyl] pyrrolidine- As a colorless gum.

1 H NMR (CDCl 3) δ : 7.61 (1H, br, d), 6.87 (1H, br, d), 4.14 (3H, br, m), 3.87 (3H, br, s), 3.41 (2H, br m), 2.22 (1H, br, m), 2.02 (2H, br, m), 1.87 (1H, br, m), 1.47 (9H, s), 1.39 (18H, s).

Intermediate 9: Methyl 3-bromo-6- bis- (tert -butoxycarbonyl) amino-2-hydroxybenzoate

Figure pct00028

Methyl 3-bromo-6-bis - (tert - butoxycarbonyl) amino-2- (4-methyl-benzenesulfonyl-oxy) dissolved benzoate (Intermediate 10, 6.2g) in methanol (200㎖) And 1 M aqueous sodium hydroxide (50 mL) was added. The mixture was stirred at room temperature for 30 minutes. The methanol was removed in vacuo and the residue was diluted with ethyl acetate and water and acidified with acetic acid. The layers were separated and the organic layer was dried (Na 2 SO 4 ) and filtered. The filtrate was concentrated in vacuo to give methyl 3-bromo-6- bis- (tert -butoxycarbonyl) amino-2-hydroxybenzoate (4.51 g) as a sand colored solid.

1 H NMR (CDCl 3 )?: 11.88 (1H, s), 7.71 (1H, d), 6.64 (1H, d), 3.96 (3H, s), 1.39 (18H, s).

Intermediate 10: Methyl 3-bromo-6- bis- (tert -butoxycarbonyl) amino-2- (4-methyl-benzenesulfonyloxy)

Figure pct00029

(Prepared according to Comess, et al , US 2004 0167128, 19.88 g) in DCM (390 ml) and triethylamine (17.96 g) was added to a solution of methyl 6-amino-3-bromo-2-hydroxybenzoate And to this was added DMAP (9.86 g) and 4-methylbenzenesulfonyl chloride (15.43 g). After stirring the resulting mixture at room temperature for 4 hours, washed, and dried (MgSO 4), and filtered water. The filtrate was concentrated in vacuo to give a yellow gum (48.2 g). The gum was dissolved in acetonitrile (390 ml) and DMAP (9.86 g), di- tert -butyl dicarbonate (37.17 g) was added and the resulting mixture was stirred at room temperature overnight. Additional di- tert -butyl dicarbonate (14.5 g) was added and the mixture was stirred for an additional hour at room temperature. The mixture was concentrated in vacuo and then the residue was taken up in ethyl acetate and aqueous citric acid (10%), washed with aqueous sodium bicarbonate solution and brine, and then, followed by drying (MgSO 4) and filtered. The filtrate was concentrated in vacuo and the residue was triturated with ether and cyclohexane (4: 1, 100 mL) and then the resulting solid was filtered off. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica eluting with a gradient of 0 to 60% using a mixture of ethyl acetate and cyclohexane to give methyl 3-bromo-6- bis- (tert -Butoxycarbonyl) amino-2- (4-methylbenzenesulfonyloxy) benzoate (43.37 g) as a pale yellow powder.

1 H NMR (CDCl 3) δ : 7.78 (2H, d), 7.62 (1H, d), 7.33 (2H, d), 7.02 (1H, d), 3.81 (3H, s), 2.47 (3H, s) , 1.39 (18H, s).

Intermediate 11: Methyl (S) -7- (2-Bromo-4-fluorobenzenesulfonylamino] -2,3,3a, 4-tetrahydro-1H- benzo [b] pyrrolo [ , 4] oxazine-6-carboxylate

Figure pct00030

methyl (S) -7- (2-Bromo-4-fluorobenzenesulfonylamino] -2,3,3a, 4-tetrahydro-1H- benzo [b] pyrrolo [ , 4] oxazine-6-carboxylate (Intermediate 12) and proceeding in the same manner as Intermediate 1.

1 H NMR (CDCl 3) δ : 7.90 (1H, dd), 7.04 (2H, m), 6.90 (1H, d), 6.77 (1H, d), 6.53 (1H, d), 6.04 (1H, m) , 4.46 (1H, dd), 3.74 (3H, s), 3.59-3.44 (2H, m), 3.31-3.12 (4H, m), 2.68 , 1.46-1.28 (1H, m), 1.06 (6H, br, t).

Intermediate 12: Methyl (S) -7- (2-Bromo-4-fluorobenzenesulfonylamino] -2,3,3a, 4-tetrahydro-1H- benzo [b] pyrrolo [ , 4] oxazine-6-carboxylate

Figure pct00031

methyl (S) -7-amino-2,3,3a, 4-tetrahydro-1H-benzo [b] pyrrolo [ ) And 2-bromo-4-fluorobenzenesulfonyl chloride, proceeding in the same manner as intermediate 2.

1 H NMR (CDCl 3) δ : 8.28 (1H, br, s), 7.96 (1H, dd), 7.40 (1H, dd), 7.03 (2H, m), 6.48 (1H, d), 4.43 (1H, m), 1.46-1.33 (1 H, m), 3.13 (1 H, td), 3.85 (3H, s), 3.57-3.39 .

Intermediate 13: Methyl (S) -7-amino-2,3,3a, 4-tetrahydro-1H- benzo [b] pyrrolo [

Figure pct00032

methyl Was prepared by proceeding in the same manner as Intermediate 6, starting from 6-amino-3-bromo-2- ((S) -1-pyrrolidin-2-ylmethoxy) benzoate (Intermediate 14).

LCMS (Method A) rt 2.10 (M + H) 249

Intermediate 14: Methyl 6-Amino-3-bromo-2 - ((S) -1-pyrrolidin-2-ylmethoxy) benzoate

Figure pct00033

tert -butyl (Intermediate 15) was added to a solution of (S) -2- [6-bromo-3- (tert -butoxycarbonyl) amino-2-methoxycarbonylphenoxymethyl] pyrrolidine- And proceeding in the same manner as in the intermediate product 7. [

LCMS (Method A) r / t 2.02 (M + H) 329/331

Intermediate 15: tert -Butyl (S) -2- [6-bromo-3- bis- (tert -butoxycarbonyl) amino-2- methoxycarbonylphenoxymethyl] pyrrolidine-

Figure pct00034

tert -butyl (R) -2-hydroxymethylpyrrolidine-1-carboxylate and methyl 3-bromo-6- bis- (tert -butoxycarbonyl) amino-2-hydroxybenzoate Starting from product 9), proceeding in the same manner as intermediate product 8.

1 H NMR (CDCl 3) δ : 7.60 (1H, br, d), 6.85 (1H, br, d), 4.17-4.07 (3H, br, m), 3.86 (3H, br, s), 3.41 (2H br, m), 2.21 (1H, br, m), 2.00 (2H, d), 1.87 (1H, br, s), 1.47 (9H, s), 1.38 (18H, s).

Intermediate 16: Methyl 7- [2- ((Z) -3-diethylaminoprop-1-enyl) -4-fluorobenzenesulfonylamino] -2,3-dihydro-lH-pyrrolo [ 1,2-a] indole-8-carboxylate

Figure pct00035

To a solution of methyl 7- (2-bromo-4-fluorobenzenesulfonylamino) -2,3-dihydro-lH-pyrrolo [1,2-a] indole 8-carboxylate (intermediate 17, 0.100g) and N, N - diethyl -N - ((Z) -1-tributylamine Stan nanil prop-1-en-3-yl) -amine (intermediate 3, 0.172 g) was degassed and purged with nitrogen. Tris- (dibenzylideneacetone) -dipalladium (0.009 g) and tri- tert -butylphosphonium tetrafluoroborate (0.006 g) And the reaction mixture was heated at 95 DEG C for 45 minutes under a nitrogen atmosphere. After cooling, the mixture was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. the combined dried (MgSO 4), and filtered, and the filtrate was concentrated in vacuo. the residue was eluted using a mixture of methanol and DCM with a gradient of 0 to 7.5% The key was purified by chromatography on silica to give methyl 7- [2- ((Z) -3-diethylaminoprop-1-enyl) -4-fluorobenzenesulfonylamino] -2,3-dihydro -LH-pyrrolo [l, 2-a] indole-8-carboxylate (0.097 g) as a yellow oil.

1 H NMR (CDCl 3) δ : 10.96 (1H, br, s), 8.10 (1H, dd), 7.25 (2H, s), 7.02 (2H, m), 6.93 (1H, d), 6.52 (1H, (2H, t), 2.61 (4H, br, m), 1.63 (3H, s), 6.05 (1H, m), 1.25 (1H, m), 0.98 (6H, m).

Intermediate 17: Methyl 7- (2-bromo-4-fluorobenzenesulfonylamino) -2,3-dihydro-lH-pyrrolo [1,2- a] indole-8-

Figure pct00036

Amino-2,3-dihydro-lH-pyrrolo [l, 2-a] indole-8-carboxylate (intermediate 18, 0.300 g) and A mixture of 2-bromo-4-fluorobenzenesulfonyl chloride (0.427 g) was stirred at room temperature for 30 minutes. The resulting mixture was diluted with ethyl acetate and washed with aqueous potassium carbonate solution (10%) and brine. After the organic layer was dried (MgSO 4), filtered, and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica eluting with a gradient of 0 to 2% using a mixture of methanol and DCM to give methyl 7- (2-bromo-4-fluorobenzenesulfonylamino) -2, 3-dihydro-lH-pyrrolo [l, 2-a] indole-8-carboxylate (0.350 g) as a white foam.

1 H NMR (CDCl 3) δ : 11.33 (1H, br, s), 8.23 (1H, dd), 7.38-7.29 (2H, m), 7.23 (1H, d), 7.07 (1H, ddd), 6.55 ( 1H, d), 4.03 (2H, t), 4.01 (3H, s), 3.03 (2H, t), 2.66-2.55 (2H, m).

Intermediate 18: Methyl 7-amino-2,3-dihydro-lH-pyrrolo [1,2-a] indole-8-

Figure pct00037

To a solution of methyl 7-nitro-2,3-dihydro-lH-pyrrolo [l, 2-a] indole-8-carboxylate (intermediate 19, 0.160 g) in methanol (6 ml) And tin (II) chloride (0.520 g) was heated at 60 &lt; 0 &gt; C for 8 hours. The resulting mixture was cooled, diluted with DCM and then filtered through Celite. The filtrate was washed with 1 M aqueous sodium hydroxide solution and brine, dried (MgSO 4 ) and filtered. The filtrate was concentrated in vacuo to give methyl 7-amino-2,3-dihydro-lH-pyrrolo [1,2-a] indole-8-carboxylate (0.100 g) as a brown solid.

1 H NMR (CDCl 3) δ : 7.19 (1H, dd), 6.55 (1H, d), 6.47 (1H, d), 5.9-5.4 (2H, br, s), 4.03 (2H, t), 3.96 ( 3H, s), 3.02 (2H, t), 2.64-2.53 (2H, m).

Intermediate 19: Methyl 7-nitro-2,3-dihydro-lH-pyrrolo [1,2-a] indole-8-

Figure pct00038

Sodium hydride (60% dispersion in oil, 0.096 g) was added to a solution of methyl 2- (3-methanesulfonyloxypropyl) -5-nitro-lH-indole- 0.460 g) and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was diluted with ethyl acetate and water, washed with brine, dried (MgSO 4 ) and filtered. The filtrate was concentrated in vacuo to give methyl 7-nitro-2,3-dihydro-lH-pyrrolo [l, 2-a] indole-8-carboxylate (0.320 g) as a brown solid.

1 H NMR (CDCl 3) δ : 7.89 (1H, d), 7.28 (1H, dd), 6.36 (1H, m), 4.14 (2H, t), 4.00 (3H, s), 3.10-3.03 (2H, m), 2.68 (2 H, m).

Intermediate 20: Methyl 2- (3-methanesulfonyloxypropyl) -5-nitro-1 H-indole-4-carboxylate

Figure pct00039

Methanesulfonyl chloride (0.176 g) was added to a solution of methyl 2- (3-hydroxypropyl) -5-nitro-lH-indole-4-carboxylate (intermediate 21, , And the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with DCM and washed with aqueous citric acid (5%), aqueous sodium bicarbonate and brine, dried (MgSO 4) and then, filtered. The filtrate was concentrated in vacuo and the residue was dissolved in toluene and then evaporated to dryness four times to give methyl 2- (3-methanesulfonyloxypropyl) -5-nitro-1H-indole- Carboxylate (0.460 g) as an orange gum.

1 H NMR (CDCl 3) δ : 7.88 (1H, d), 7.41 (1H, dd), 6.46 (1H, s), 4.31 (2H, t), 4.01 (3H, s), 3.05 (3H, s) , 2.97 (2H, t), 2.19 (2H, m).

Intermediate 21: Methyl 2- (3-hydroxypropyl) -5-nitro-1 H-indole-4-carboxylate

Figure pct00040

(Intermediate 22, 0.650 g) was dissolved in methanol (1.25 M, 18 ml) and a solution of methyl 5-nitro-2- [3- (tetrahydropyran- Was dissolved in a solution of hydrogen chloride and the resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and aqueous potassium carbonate solution (10%). The aqueous layer was extracted with ethyl acetate, then washed with brine and then combined organic layers, dried (MgSO 4), and filtered. The filtrate was concentrated in vacuo to give methyl 2- (3-hydroxypropyl) -5-nitro-lH-indole-4-carboxylate (0.388 g) as a dark orange gum.

1 H NMR (CDCl 3) δ : 9.19 (1H, br, s), 7.89 (1H, d), 7.37 (1H, dd), 6.44 (1H, m), 4.02 (3H, s), 3.81 (2H, m), 2.97 (2H, t), 2.86 (1H, t), 2.00 (2H, m).

Intermediate 22: Methyl 5-nitro-2- [3- (tetrahydropyran-2-yloxy) -propyl] -1H-indole-

Figure pct00041

Potassium tert -butoxide (0.230 g) was added to a solution of methyl 3-acetylamino-6-nitro-2- [5- (tetrahydropyran-2- yloxy) ) -Pent-1-ynyl] benzoate (intermediate 23, 0.70 g) in dichloromethane and the reaction mixture was heated at 70 &lt; 0 &gt; C for 1 hour. After cooling, dilute the mixture with ethyl acetate, washed with water and brine, then dried (MgSO 4), and filtered. The filtrate was concentrated in vacuo to give methyl 5-nitro-2- [3- (tetrahydropyran-2-yloxy) -propyl] -1H-indole-4-carboxylate (0.530 g) as a dark orange gum Respectively.

1 H NMR (CDCl 3) δ : 9.84 (1H, br, s), 7.87 (1H, d), 7.29 (1H, dd), 6.41 (1H, m), 4.60 (1H, m), 4.06-4.00 ( M), 4.00 (3H, s), 3.90-3.80 (1H, td), 3.60 (2H, m), 3.00-2.90 (2H, m), 2.11-1.78 (8H, m).

Intermediate 23: Methyl 3-acetylamino-6-nitro-2- [5- (tetrahydropyran-2- yloxy) -pent- 1 -inyl] benzoate

Figure pct00042

A solution of methyl 3-acetylamino-2-bromo-6-nitrobenzoate (prepared according to WO 2004/046198 of Ninkovic et al., 7.1 g) and tributyl- [5- (Tetrahydropyran-2-yloxy) -pent-1-ynyl] -stannane (intermediate 24, 20.5 g) was degassed and purged with nitrogen. Tris- (dibenzylideneacetone) -dipalladium (1.02 g) and tri- tert -butylphosphonium tetrafluoroborate (0.650 g) were added and the mixture was heated at 50 ° C for 30 minutes. After cooling, the mixture was diluted with DCM and filtered through celite. After washing the filtrate with water and brine, dried (MgSO 4), and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica eluting with a gradient of 0-100% using a mixture of ethyl acetate and cyclohexane to give methyl 3-acetylamino-6-nitro- 2- [5- (Tetrahydropyran-2-yloxy) -pent-1-ynyl] benzoate (8.75 g) as a black gum.

1 H NMR (CDCl 3) δ : 8.65 (1H, d), 8.23 (1H, br, s), 8.12 (1H, d), 4.60 (1H, t), 3.98 (3H, s), 3.95-3.81 ( 2H), 3.57-3.47 (2H, m), 2.68 (2H, t), 2.29 (3H, s), 2.02-1.89 (2H, m), 1.86-1.66 4H, m).

Intermediate 24: Tributyl- [5- (tetrahydropyran-2-yloxy) -pent-1-ynyl] -stannane

Figure pct00043

A solution of n-butyllithium (2.5 M in hexanes, 22 mL) in THF (60 mL) was added to a solution of 2- (pent-4-ynyloxy) tetrahydropyran (intermediate 25, 7.70 g) Lt; / RTI &gt; was added dropwise. The mixture was stirred and allowed to warm to 15 DEG C over 1 hour. It was then recooled to-60 C and added dropwise over 30 minutes to a solution of tributyltin chloride (16.4 g) in THF (50 mL). The mixture was stirred and allowed to warm to 20 占 폚 over 1 hour. 1 M aqueous sodium hydroxide (4 mL) was carefully added and the resulting mixture was filtered through celite then washed with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica eluting with a gradient of 0-100% using a mixture of ethyl acetate and cyclohexane to give tributyl- [5- (tetrahydropyran- Yloxy) -pent-1-ynyl] -stannane (5.44 g).

1 H NMR (CDCl 3) δ : 4.60 (1H, t), 3.89-3.77 (2H, m), 3.54-3.40 (2H, m), 2.37-2.26 (2H, m), 1.81 (3H, m), 1.55 (10H, m), 1.38 (7H, m), 0.94-0.81 (15H, m).

Intermediate 25: 2- (Pent-4-ynyloxy) tetrahydropyran

Figure pct00044

3,4-Dihydro-2H-pyran (5.0 g) was added dropwise to a ice-cooled mixture of 4-pentyn-1-ol (5.0 g) and 4-methylbenzenesulfonic acid (0.512 g). The resulting mixture was stirred at room temperature for 4 hours. Solid sodium bicarbonate (1.0 g) was added and the mixture was stirred for 10 min, then filtered and washed with diethyl ether. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica eluting with a gradient of 0-100% using a mixture of ethyl acetate and cyclohexane to give 2- (pent-4-ynyloxy) tetra Hydropyrane (7.72 g) as a clear oil.

1 H NMR (CDCl 3) δ : 4.61 (1H, t), 3.93-3.79 (2H, m), 3.57-3.45 (2H, m), 2.36-2.29 (2H, m), 1.95 (1H, t), 1.89-1.67 (4 H, m), 1.64-1.49 (4 H, m).

Intermediate 26: Methyl 7- benzenesulfonylamino-2,3-dihydro-lH-pyrrolo [1,2-a] indole-8-

Figure pct00045

Benzenesulfonyl chloride (0.092 g) was added to a solution of methyl 7-amino-2,3-dihydro-lH-pyrrolo [l, 2-a] indole-8-carboxylate (Intermediate 18, 0.100 g) and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was diluted with ethyl acetate, washed with aqueous potassium carbonate solution, dried (MgSO 4 ) and filtered. The filtrate was concentrated in vacuo, then dissolved in toluene and re-evaporated to dryness. The residue was purified by chromatography on silica eluting with a gradient of 0 to 2% using a mixture of ammonia and DCM in methanol (2M). The resulting solid was triturated with diethyl ether to give methyl 7-benzenesulfonylamino-2,3-dihydro-lH-pyrrolo [l, 2-a] indole-8-carboxylate (0.078 g) as a cream-colored powder.

1 H NMR (CDCl 3 )?: 10.47 (1H, br, s), 7.72 (2H, m), 7.55 (1H, d), 4.07 (2H, t), 3.86 (3H, s), 3.02 (2H, t), 2.62 (2H, m).

Intermediate 27: Methyl 7- [2 - ((Z) -3-diethylaminoprop-1-en-1-yl) -4-fluorobenzenesulfonylamino] -2,3,9,9a-tetrahydro- Pyrrolo [l, 2-a] indole-8-carboxylate

Figure pct00046

methyl Pyrrolo [l, 2-a] indole-8-carboxylate (Intermediate 28 &lt; RTI ID = 0.0 & ) and N, N-diethyl -N - ((Z) -1-butyl-trimethyl-prop-1-en-3-yl nanil Stan), starting from the amine (intermediate 3), similar to the intermediate product 1 . &Lt; / RTI &gt;

1 H NMR (CDCl 3) δ : 8.02 (1H, m), 7.17 (1H, d), 7.04 (2H, m), 6.95 (1H, d), 6.58 (1H, d), 6.00 (1H, br, m), 3.87 (1H, br, m), 3.83 (3H, s), 3.41-3.23 (2H, m), 3.20-2.97 2H, m), 1.33-1.16 (2H, m), 0.96 (6H, br, t).

Intermediate 28: Methyl 7- (2-bromo-4-fluorobenzenesulfonylamino) -2,3,9,9a-tetrahydro- lH-pyrrolo [1,2- a] indole-8-

Figure pct00047

A solution of methyl 7-amino-2,3,9,9a-tetrahydro-lH-pyrrolo [l, 2-a] indole-8-carboxylate (intermediate 29, 0.400 g) and 2-bromo-4-fluorobenzenesulfonyl chloride (0.565 g) was stirred at room temperature for 30 minutes. After diluting the mixture with ethyl acetate and washed with aqueous potassium carbonate solution (10%) and brine, then dried (MgSO 4), and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica eluting with a gradient of 0 to 2% using a mixture of methanol and DCM. The resulting solid was redissolved by chromatography on silica eluting with a gradient of 0-100% using a mixture of ethyl acetate and cyclohexane containing 1% triethylamine to give a yellow solid which was dissolved in DCM and cyclo Hexane (50%) followed by chromatography again on silica eluting with DCM (100%). The resulting solid was purified by chromatography on silica eluting with a gradient of 5-30% using a mixture of ethyl acetate and cyclohexane to give methyl Pyrrolo [l, 2-a] indole-8-carboxylate (0.317 g) was obtained as white crystals from 7- (2-bromo-4-fluorobenzenesulfonylamino) -2,3,9,9a-tetrahydro- As a black gum.

1 H NMR (CDCl 3) δ : 10.25 (1H, br, s), 8.13 (1H, dd), 7.38 (1H, m), 7.29 (1H, d), 7.08 (1H, m), 6.56 (1H, d), 3.88 (4H, m), 3.41-3.27 (2H, m), 3.17 (1H, dd), 3.02 (1H, m), 1.92-1.76 (3H, m), 1.26

Intermediate 29: Methyl 7-amino-2,3,9,9a-tetrahydro-lH-pyrrolo [1,2-a] indole-8-

Figure pct00048

A) indole-8-carboxylate (intermediate 30, 1.01 g) was dissolved in ethanol (38 &lt; RTI ID = 0.0 & ). &Lt; / RTI &gt; Palladium on activated charcoal (10%, 0.100 g) was added and the nitrogen atmosphere was replaced with hydrogen. The mixture was then stirred under a hydrogen atmosphere for 18 hours. The resulting mixture was filtered through celite and the filtrate was concentrated in vacuo to give an orange oil (1.41 g). This was partitioned between ethyl acetate and 1M aqueous sodium hydroxide. The aqueous layer was extracted with ethyl acetate, dried the combined organic layer (MgSO 4), and filtered, and the filtrate was concentrated in vacuo to give 7-amino-methyl -2,3,9,9a- tetrahydro -1H- pyrrolo [1,2-a] indole-8-carboxylate (0.818 g) as a dark orange oil.

1 H NMR (CDCl 3) δ : 6.67 (1H, d), 6.53 (1H, d), 3.95-3.87 (1H, m), 3.86 (3H, s), 3.44-3.32 (2H, m), 3.29- 3.19 (1H, m), 3.10-2.98 (1H, m), 1.97-1.86 (1H, m), 1.85-1.73 (2H, m), 1.44-1.30 (1H, m).

Intermediate 30: Methyl 7-nitro-2,3,9,9a-tetrahydro-lH-pyrrolo [l, 2-a] indole-8-

Figure pct00049

(Intermediate 19, 1.00 g) was dissolved in TFA (100 mL) and sodium triflate was added dropwise to a solution of methyl 7-nitro-2,3-dihydro- lH- pyrrolo [ Lt; / RTI &gt; (8.11 g) was added. The reaction mixture was stirred at room temperature, then diluted with toluene and concentrated in vacuo. After extraction the residue was dissolved in ethyl acetate and an aqueous potassium carbonate solution, dried (MgSO 4) and then, filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica eluting with a gradient of 0 to 2% using a mixture of methanol and DCM to give methyl 7-nitro-2,3,9,9a -Tetrahydro-lH-pyrrolo [l, 2-a] indole-8-carboxylate (1.66 g) as a black gum.

1 H NMR (CDCl 3) δ : 8.06 (1H, d), 7.21 (1H, d), 4.62 (1H, m), 3.96 (3H, s), 3.90 (1H, m), 3.51 (1H, dd) , 3.31 (1H, dt), 3.14 (1H, dd), 2.31 (1H, m), 2.18-2.07 (2H, m), 1.70 (1H, m).

Intermediate 31: Methyl 7- [2- ((Z) -3-diethylaminoprop-1-enyl) -4-fluorobenzenesulfonylamino] -1,2,3,3a, 4,5- Hexahydropyrrolo [1,2-a] quinoline-6-carboxylate

Figure pct00050

To a solution of methyl 7- (2-bromo-4-fluorobenzenesulfonylamino) -1,2,3,3a, 4,5-hexahydro-pyrrolo [1 , 2-a] quinoline-6-carboxylate (intermediate 32, 0.483 g) and N, N - diethyl- -Amine (Intermediate 3, 0.804 g) was purged with nitrogen and then treated with tris- (dibenzylideneacetone) dipalladium (0) (0.046 g) and tri- tert -butylphosphonium tetrafluoroborate 0.029 g). The reaction mixture was heated at 95 占 폚 and stirred under a nitrogen atmosphere for 1 hour. After cooling, dilute the mixture with ethyl acetate and washed with water, dried (Na 2 SO 4) and then, filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica eluting with a gradient of 0 to 25% using a mixture of methanol and DCM to give methyl 7- [2 - ((Z) -3- Diethylaminoprop-1-enyl) -4-fluorobenzenesulfonylamino] -1,2,3,3a, 4,5-hexahydropyrrolo [1,2- a] quinoline- (0.480 g) as a yellow gum.

1 H NMR (CDCl 3) δ : 7.88 (1H, dd), 7.00 (3H, m), 6.77 (1H, d), 6.38 (1H, d), 6.01 (1H, m), 3.69 (3H, s) (1H, m), 3.20-3.45 (5H, m), 3.15 (1H, m), 2.59-2.81 (5H, m), 2.20 , &lt; / RTI &gt; m), 1.07 (6H, br, t).

Intermediate 32: Methyl 7- (2-bromo-4-fluorobenzenesulfonylamino) -1,2,3,3a, 4,5-hexahydro-pyrrolo [ - carboxylate

Figure pct00051

2-Bromo-4-fluorobenzenesulfonyl chloride (0.656 g) was added to a solution of methyl 7-amino-1,2,3,3a, 4,5-hexahydrofuran 2-a] quinoline-6-carboxylate (intermediate product 33, 0.575 g) in dichloromethane and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water, and the organic layer was dried (Na 2 SO 4) and then, filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica eluting with a gradient of 0 to 25% using a mixture of ethyl acetate and cyclohexane to give a light yellow solid which was dissolved in ether : 1) to give methyl 7- (2-bromo-4-fluorobenzenesulfonylamino) -1,2,3,3a, 4,5-hexahydropyrrolo [1,2- a ] Quinoline-6-carboxylate (0.966 g).

1 H NMR (CDCl 3) δ : 7.94 (1H, dd), 7.70 (1H, br, s), 7.43 (1H, dd), 7.09 (1H, d), 7.04 (1H, dt), 6.33 (1H, (2H, m), 2.01-2.18 (3H, m), 1.89 (1H, d), 3.82 (1 H, m), 1.19-1.44 (2 H, m).

Intermediate 33: methyl; 7-Amino-1,2,3,3a, 4,5-hexahydropyrrolo [1,2-a] quinoline-6-

Figure pct00052

Sulfuric acid (5 ml) was added to a solution of methyl 7- (2,2-dimethyl-propionylamino) -1,2,3,3a, 4,5-hexahydropyrrolo [ ] Quinoline-6-carboxylate (intermediate product 34, 0.820 g) in dichloromethane (1 mL) and the resulting mixture was stirred and heated at reflux for 4 hours and then allowed to stand at room temperature for 4 days. This mixture was then heated under reflux for a further 1.5 hours. After cooling, the solution was evaporated in vacuo and the residue was partitioned between ethyl acetate and water and basified with 20% aqueous sodium hydroxide solution. The organic layer was dried (Na 2 SO 4), then filtered, and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica eluting with a gradient of 0-30% using a mixture of ethyl acetate and cyclohexane to give methyl 7-amino-1,2,3,3a, 4,5-hexahydro -Pyrrolo [1,2-a] quinoline-6-carboxylate (0.580 g) as a yellow gum.

LCMS (Method A) r / t 2.11 (M + H) 247

Intermediate 34: Methyl 7- (2,2-dimethylpropionylamino) -1,2,3,3a, 4,5-hexahydropyrrolo [1,2-a] quinoline-

Figure pct00053

To a solution of methyl 3-bromo-6- (2,2-dimethylpropionylamino) -2- (2-pyrrolidin-2-yl-ethyl) -benzoate (intermediate 35, 2.05 g), palladium acetate (0.282 g), cesium carbonate (3.26 g) and 2,2'- bis (diphenylphosphino) -1,1'-binaphthalene (1.557 g) Lt; 0 &gt; C for a period of time. After cooling, dilute the mixture with ethyl acetate and, after washed with water, dried (Na 2 SO 4) and then, filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica eluting with a gradient of 0 to 30% using a mixture of ethyl acetate and cyclohexane to give methyl 7- (2,2-dimethylpropyl) Quinolin-6-carboxylate (0.826 g) as a light yellow solid, MS (ISP): m / e calcd for &lt;

LCMS (Method A) r / t 4.01 (M + H) 331

Intermediate 35: Methyl 3-bromo-6- (2,2-dimethylpropionylamino) -2- (2-pyrrolidin-

Figure pct00054

Trifluoroacetic acid (15 ml) was added to a solution of tert -butyl 2- {2- [6-bromo-3- (2,2-dimethylpropionylamino) -2- methoxycarbonylphenyl ] -Ethyl} -pyrrolidine-1-carboxylate (intermediate product 36, 2.54 g) in dichloromethane and the mixture was allowed to stand at room temperature for 30 minutes. The resulting solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and potassium carbonate solution. The organic layer was dried (Na 2 SO 4), then filtered, the filtrate was concentrated in vacuo to methyl 3-bromo-6- (2,2-dimethyl-propionylamino) -2- (2-pyrrolidin- 2-yl-ethyl) benzoate (2.05 g) as a white foam.

1 H NMR (CDCl 3) δ : 8.99 (1H, br, s), 7.99 (1H, d), 7.56 (1H, d), 3.96 (3H, s), 3.48 (1H, m), 3.15-3.32 ( 2H, m), 2.83 (2H, m), 1.91-2.22 (5H, m), 1.70 (1H, m), 1.29 (9H, s).

Intermediate 36: tertbutyl 2- {2- [6-bromo-3- (2,2-dimethylpropionylamino) -2-methoxycarbonyl-phenyl] -ethyl} -pyrrolidin- Carboxylate

Figure pct00055

N-Bromosuccinimide (1.24 g) was added to a solution of tert butyl 2- {2- [3- (2,2-dimethyl-propionylamino) -2- methoxycarbonylphenyl ] -Ethyl} -pyrrolidine-1-carboxylate (intermediate 37, 2.74 g) and the resulting mixture was stirred for 1 hour at room temperature. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was dried (Na 2 SO 4), then filtered, and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica eluting with a gradient of 0 to 25% using a mixture of ethyl acetate and cyclohexane to give tert- butyl 2- {2- [6-bromo-3- (2, Dimethylpropionylamino) -2-methoxycarbonylphenyl] -ethyl} -pyrrolidine-1-carboxylate (2.55 g) as a colorless gum.

LCMS (Method A) r / t 4.82 (M-H) 509,511

Intermediate 37: tert -Butyl 2- {2- [3- (2,2-dimethylpropionylamino) -2-methoxycarbonylphenyl] -ethyl} -pyrrolidine- 1-carboxylate

Figure pct00056

Ethanol (100㎖) of tert-butyl 2- [3- (2,2-dimethyl-propionylamino) -2-methoxycarbonyl-phenyl ethynyl-carbonyl] -pyrrolidine-1-carboxylate (Intermediate 38, 3.71 g) in DMF (5 mL) was treated with 10% palladium on carbon (0.50 g) and stirred under a hydrogen atmosphere for 4 hours. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica eluting with a gradient of 0 to 20% using a mixture of ethyl acetate and cyclohexane to give tert -butyl 2- {2- [3- (2,2-dimethylpropyl) Phenyl) -ethyl} -pyrrolidine-1-carboxylate (3.21 g) as a colorless gum.

1 H NMR (CDCl 3) δ : 9.56 (1H, br, d), 8.21 (1H, d), 7.36 (1H, t), 6.98 (1H, m), 3.96 (3H, s), 3.65-3.95 ( (1H, m), 3.25-3.55 (2H, m), 2.74 (2H, m), 1.73-2.09 (4H, m), 1.52-1.74 s).

Intermediate 38: tert -Butyl 2- [3- (2,2-dimethylpropionylamino) -2-methoxycarbonylphenyl-ethynyl] -pyrrolidine-

Figure pct00057

To a solution of methyl 2- (2,2-dimethylpropionylamino) -6-trifluoromethanesulfonyloxybenzoate (intermediate 39, 3.83 g), tert -butyl 2-tri ethynyl butyl Stan nanil-pyrrolidine a mixture of l-carboxylate (intermediate 41, 5.81g), bis (triphenylphosphine) palladium (II) dichloride (0.702g) and lithium chloride (1.28g) Stirred and heated at 95 &lt; 0 &gt; C for 1 hour under nitrogen. After cooling, the mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water, dried (Na 2 SO 4 ) and then filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica eluting with a gradient of 0 to 25% using a mixture of ethyl acetate and cyclohexane to give tert -butyl 2- [3- (2, 2-dimethylpropionylamino) -2-methoxycarbonyl-phenylethynyl] -pyrrolidine-1-carboxylate (3.71 g) as a viscous gum.

LCMS (Method A) / t 4.55 (M-H) 427

Intermediate 39: Methyl 2- (2,2-dimethylpropionylamino) -6-trifluoromethanesulfonyloxy-benzoate

Figure pct00058

Trifluoromethanesulfonic anhydride (6.2 g) was added to a solution of methyl 2- (2,2-dimethylpropionylamino) -6-hydroxybenzoate (intermediate 40, 5.02 g) and pyridine 3.16 g) in a dropwise manner, and the mixture was stirred for 1 hour. The resulting solution was washed with 2M hydrochloric acid, filtered through a phase separator, and the filtrate was evaporated in vacuo. The residue was purified by chromatography on silica eluting with a gradient of 0-15% using a mixture of ethyl acetate and cyclohexane to give methyl 2- (2,2-dimethylpropionylamino) -6-trifluo (7.09 g) as a colorless oil.

1 H NMR (CDCl 3 )?: 10.66 (1H, br, s), 8.74 (1H, d), 7.56 (1H, t), 6.98 s).

Intermediate 40: Methyl 2- (2,2-dimethylpropionylamino) -6-hydroxybenzoate

Figure pct00059

Trimethylacetyl chloride (5.57 g) was added to a solution of methyl 2-amino-6-hydroxybenzoate (prepared according to Comess et al , US 2004 0167128) in a mixture of water (40 ml) and ethyl acetate (100 ml) 5.15 g) and sodium bicarbonate (7.76 g) in a dropwise manner, and the mixture was stirred for 1 hour. Trimethylacetyl chloride (5.57 g) was further added and the mixture was stirred overnight. The organic layer was separated, dried (Na 2 SO 4) and then, filtered. The filtrate was concentrated in vacuo and the residue was triturated with pentane. The resulting solid was collected by filtration and purified by chromatography on silica eluting with a gradient of 0 to 25% using a mixture of ethyl acetate and cyclohexane to give methyl 2- (2,2-dimethyl-propionyl Amino) -6-hydroxy-benzoate (4.96 g) as a white solid.

1 H NMR (CDCl 3 )?: 10.41 (1H, s), 10.31 (1H, br, s), 8.21 s), 1.34 (9H, s).

Intermediate 41: tert -Butyl 2-tributylstannanylethynyl-pyrrolidine-l-carboxylate

Figure pct00060

(1.6 M in hexanes, 12.3 ml) was added to a stirred solution of tert -butyl 2-ethynylpyrrolidine-1-carboxylate (3.65 g) in anhydrous THF (80 ml) Over 2 minutes and then the mixture was allowed to warm to -30 &lt; 0 &gt; C over 1 hour. Tributyltin chloride (6.41 g) was then added dropwise at -30 <0> C and the mixture was allowed to warm to -10 <0> C and then quenched by the addition of saturated sodium bicarbonate solution. The layers were separated and the organic layer was dried (Na 2 SO 4 ) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica eluting with a gradient of 0-5% using a mixture of ethyl acetate and cyclohexane to give tert -butyl 2-tributylstannanylethyl 1-carboxylate (5.54 g) as a colorless oil.

1 H NMR (CDCl 3) δ : 4.35-4.6 (1H, br, s), 3.45 (1H, br, s), 3.29 (1H, br, s), 1.93-2.12 (3H, br, m), 1.86 (1H, br s), 1.49-1.59 (6H, m), 1.48 (9H, s) 1.25-1.40 (6H, m), 0.95 (6H, m), 0.89 (9H, t).

Intermediate 42: tertbutyl (R) -6- [2 - ((Z) -3-Diethylaminoprop-1-enyl) -4-fluoro-benzenesulfonylamino] 3-tetrahydro-4-oxa-8b-azacyclobuta [a] naphthalene-5-carboxylate

Figure pct00061

To a solution of tert -butyl (R) -6- (2-bromo-4-fluorobenzenesulfonylamino) -1,2,2a, 3-tetrahydro- oxa-aza-cycloalkyl -8b- byuta [a] naphthalen-5-carboxylate (intermediate 43, 0.061g) and N, N - diethyl -N - ((Z) -1-prop-1-tributylamine Stan nanil en-3-yl) -amine (intermediate 3, and purging the mixture of 0.096g) with nitrogen, tris (dibenzylideneacetone) dipalladium (0) (0.006g) and tri-tert-butyl phosphonium Tetrafluoroborate (0.004 g) was added. The reaction mixture was heated at 95 &lt; 0 &gt; C under a nitrogen atmosphere for 1.5 hours. More N, N - diethyl -N - ((Z) -1-tributylamine Stan nanil prop-1-en-3-yl) -amine (intermediate 3, 0.096g), tris- (dibenzylideneacetone the -Acetone) Dipalladium (0) (0.006 g) and tri- tert -butylphosphonium tetrafluoroborate (0.004 g) were added and heating was continued for a further 17 h. After cooling, dilute the mixture with ethyl acetate and, after washed with water, dried (Na 2 SO 4) and then, filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica eluting with a gradient of 0 to 20% using a mixture of methanol and DCM to give tert -butyl (R) -6- [2- ( (Z) -3-diethylaminoprop-1-enyl) -4-fluorobenzenesulfonylamino] -1,2,2a, 3-tetrahydro-4-oxa-8b-azacyclobuta [ Naphthalene-5-carboxylate (0.017 g) as a light brown foam.

LCMS (Method A) r / t 2.76 (M + H) 546

Intermediate 43: tert -Butyl (R) -6- (2-Bromo-4-fluorobenzenesulfonylamino) -1,2,2a, 3-tetrahydro-4-oxa-8b-azacyclobuta [ a] naphthalene-5-carboxylate

Figure pct00062

2-Bromo-4-fluorobenzenesulfonyl chloride (0.091 g) was added to a solution of tert -butyl (R) -6-amino-1,2,2a, 3-tetra Oxa-8b-azacyclobuta [a] naphthalene-5-carboxylate (intermediate 44, 0.092 g) in dichloromethane and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo and the residue was partitioned between DCM and 1 M hydrochloric acid and filtered through a phase separator. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica eluting with a gradient of 0 to 25% using a mixture of ethyl acetate and cyclohexane to give tert -butyl (R) -6- (2 [Alpha]] naphthalene-5-carboxylate (0.062 g) was obtained as a colorless amorphous solid Respectively.

LCMS (Method A) r / t 4.31 (M + H) 513, 515

Intermediate 44: tert -Butyl (R) -6-amino-1,2,2a, 3-tetrahydro-4-oxa-8b-azacyclobuta [a] -naphthalene-

Figure pct00063

A solution of tert -butyl (R) -6-benzyloxycarbonylamino-1,2,2a, 3-tetrahydro-4-oxa-8b-aza-cyclobuta [a] naphthalene- A solution of the intermediate (45, 0.138 g) in water was treated with 10% palladium on carbon (0.05 g) and the resulting mixture was stirred under a hydrogen atmosphere for 30 minutes. The mixture was filtered and the filtrate was concentrated in vacuo to give tert -butyl (R) -6-amino-1,2,2a, 3-tetrahydro-4-oxa-8b-azacyclobuta [ 5-carboxylate (0.092 g) as a light yellow solid.

LCMS (Method A) r / t 2.27.

Intermediate 45: tert-Butyl (R) -6-Benzyloxycarbonylamino-1,2,2a, 3-tetrahydro-4-oxa-8b-aza-cyclobuta [a] naphthalene-

Figure pct00064

To a solution of tert -butyl 2 - ((R) -l-azetidin-2-ylmethoxy) -6- benzyloxycarbonylamino-3-bromo-benzoate (intermediate 46, 1.46 g) in toluene (35 ml) , Palladium acetate (0.167 g), cesium carbonate (1.935 g) and 2,2'-bis (diphenylphosphino) -1,1'-binaphthalene (0.925 g) was stirred and heated under nitrogen for 4 hours Lt; 0 &gt; C. After cooling, the mixture was diluted with ethyl acetate and water and filtered through celite. After the organic layer was separated, dried (Na 2 SO 4), filtered, and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica eluting with a gradient of 5-40% using a mixture of ethyl acetate and cyclohexane to give tert -butyl (R) -6-benzyloxycarbonylamino- 2a, 3-tetrahydro-4-oxa-8b-azacyclobuta [a] naphthalene-5-carboxylate (0.141 g) as an off-white solid.

1 H NMR (CDCl 3) δ : 8.31 (1H, br, s), 7.56 (1H, br d), 7.29-7.41 (5H, m), 6.73 (1H, br, d), 5.18 (2H, s) , 4.34 (1H, dd), 4.24 (2H, br, m), 3.72 (2H, m), 2.73 (2H, m), 1.59 (9H, s).

Intermediate 46: tert -Butyl 2 - ((R) -1-azetidin-2-ylmethoxy) -6- benzyloxycarbonylamino-3-bromobenzoate

Figure pct00065

To a solution of tert -butyl (R) -2- (3-benzyloxycarbonylamino-6-bromo-2- tert -butoxycarbonyl-phenoxymethyl) azetidine- 1 -carboxylate A solution of the intermediate (47, 1.74 g) and 4-methylbenzenesulfonic acid (0.570 g) was allowed to stand at room temperature for 18 hours. Additional 4-methylbenzenesulfonic acid (0.50 g) was added and after a further 1 hour additional 4-methylbenzenesulfonic acid (0.50 g) was added. After 1.5 h, the solution was diluted with ethyl acetate, washed with potassium carbonate solution, dried (Na 2 SO 4 ) and filtered. The filtrate was concentrated in vacuo and the residue was triturated with ether. After filtration, the filtrate was concentrated in vacuo to give tert -butyl 2 - ((R) -1-azetidin-2-ylmethoxy) -Benzyloxycarbonylamino-3-bromobenzoate (1.46 g) as a colorless oil.

LCMS (Method A) r / t 2.76 (M-H) 489,491.

Intermediate 47: tert-butyl (R) -2- (3- benzyloxy-carbonyl-amino-6-bromo -2- tert-butoxycarbonylamino-phenoxymethyl) -azetidine-1-carboxylate

Figure pct00066

Diisopropyl azodicarboxylate (0.717 g) was added to tert -butyl 6-benzyloxycarbonylamino-3-bromo-2-hydroxybenzoate (intermediate 48, 1.25 g) in anhydrous THF was added to a solution of tert -butyl (R) -2-hydroxymethylazetidine-1-carboxylate (0.665 g) and triphenylphosphine (0.93 g) and the resulting mixture was stirred at room temperature for 30 minutes. The solution was concentrated in vacuo and the residue was purified by chromatography on silica eluting with a gradient of 0 to 20% using a mixture of ethyl acetate and cyclohexane to give tert -butyl (R) -2- (3 -Benzyloxycarbonylamino-6-bromo-2- tert -butoxycarbonylphenoxymethyl) -azetidine-1-carboxylate (1.74 g) as a colorless gum.

1 H NMR (CDCl 3 )?: 8.26 (1H, br, s), 7.79 (1H, d), 7.55 (1H, d), 7.30-7.40 1H), 4.23 (2H, m), 3.89 (2H, t), 2.29-2.49 (2H, m), 1.61 (9H, s), 1.42 (9H, s).

Intermediate 48: tert -Butyl 6-benzyloxycarbonylamino-3-bromo-2-hydroxybenzoate

Figure pct00067

Potassium carbonate (5.39 g) was added to a solution of tert -butyl 6-benzyloxycarbonylamino-3-bromo-2- (4-methylbenzenesulfonyloxy) benzoate Product 49, 4.5 g) in dichloromethane (5 ml) and the resulting mixture was stirred at room temperature for 1 hour. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate and water and acidified with acetic acid. After the organic layer was separated, washed with saturated sodium bicarbonate solution, dried (Na 2 SO 4) and then, filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica eluting with a gradient of 0-15% using a mixture of ethyl acetate and cyclohexane to give tert -butyl 6-benzyloxycarbonyl-amino -3-bromo-2-hydroxybenzoate (2.5 g) as a white solid.

1 H NMR (CDCl 3) δ : 11.81 (1H, s), 9.68 (1H, br, s), 7.83 (1H, d), 7.60 (1H, d), 7.30-7.40 (5H, m), 5.20 ( 2H, s), 1.67 (9H, s).

Intermediate 49: tert -Butyl 6-benzyloxycarbonylamino-3-bromo-2- (4-methylbenzenesulfonyl-oxy)

Figure pct00068

Benzyl chloroformate (1.705 g) was added to a solution of tert -butyl 6-amino-3-bromo-2- (4-methylbenzenesulfonyloxy) -benzoate (intermediate 50 , 3.8g). The mixture was stirred for 1 hour and further benzyl chloroformate (1.70 g) was added. The mixture was stirred for an additional hour, and further benzyl chloroformate (1.70 g) was added. After stirring for an additional 30 min, the solution was concentrated in vacuo and the residue was dissolved in DCM and 1 M hydrochloric acid and then filtered through a phase separator. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica eluting with a gradient of 0-15% using a mixture of ethyl acetate and cyclohexane to give tert -butyl 6-benzyloxycarbonylamino- 3-Bromo-2- (4-methylbenzenesulfonyloxy) benzoate (4.91 g) as a white solid.

1 H NMR (CDCl 3 )?: 9.67 (1H, br, s), 8.18 (1H, d), 7.65 (2H, d), 7.31-7.46 2H, s), 2.46 (3H, s), 1.68 (9H, s).

Intermediate 50: tert -Butyl 6-amino-3-bromo-2- (4-methylbenzenesulfonyloxy) benzoate

Figure pct00069

Methylbenzenesulfonyl chloride (2.26 g) was added to tert-butyl 6-amino-3-bromo-2-hydroxybenzoate (intermediate 51, 2.85 g), DMAP (1.21 g) in DCM And triethylamine (1.5 g) in DMF (2 ml) and allowed to stand at room temperature for 1 hour. The resulting solution was washed with water, filtered through a phase separator, and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica eluting with a gradient of 0-15% using a mixture of ethyl acetate and cyclohexane to give tert -butyl 6-amino-3-bromo-2- (4-methylbenzene Sulfonyloxy) benzoate (3.51 g) as an off-white solid.

1 H NMR (CDCl 3) δ : 7.68 (2H, d), 7.28 (2H, d), 7.15 (1H, d), 6.47 (1H, d), 3.0-4.6, (2H, br, s), 2.44 (3H, s), 1.66 (9H, s).

Intermediate 51: tert- Butyl 6-amino-3-bromo-2-hydroxybenzoate

Figure pct00070

Dicyclohexyl carbodiimide (4.14g) the tert - 6- amino-3-bromo-2-hydroxybenzoic acid of the butanol (20㎖) and THF (150㎖) (intermediate 63, 3.88g) and DMAP (0.102 g). The mixture was stirred at room temperature for 4 hours. The obtained precipitate was filtered off and washed with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica eluting with a gradient of 2.5-15% using a mixture of ethyl acetate and cyclohexane to give tert- butyl 6-amino-3-bromo -2-hydroxybenzoate (1.16 g) as a yellow solid.

1 H NMR (CDCl 3 )?: 11.99 (1H, s), 7.30 (1H, d), 6.06 (1H, d), 5.35 (2H, s), 1.65

Intermediate 52: 6-Amino-3-bromo-2-hydroxybenzoic acid

Figure pct00071

Hydroxybenzoate ( prepared according to Wang et al , Bioorg Med Chem Lett, 2007, 17, 2817, 5.41 g) and lithium hydroxide monohydrate (9.23 g, ) Was suspended in dioxane (100 mL) and water (100 mL) and heated at 80 &lt; 0 &gt; C overnight. The temperature was then increased to 100 DEG C for 4 hours. Further lithium hydroxide monohydrate (4.61 g) was added and the reaction mixture was heated at 100 &lt; 0 &gt; C for an additional hour. After cooling, the mixture was concentrated in vacuo and the residue was acidified to pH 3 with formic acid and then extracted with ethyl acetate. The organic layer was dried (MgSO 4), then filtered, the filtrate was concentrated in vacuum to 6-amino-3-bromo-2-hydroxybenzoic acid (6.22g) solution was obtained as a black / gray solid.

1 H NMR (DMSO-d 6 )?: 7.24 (1H, d), 6.16 (1H, d).

Intermediate 53: Methyl 6- [2 - ((Z) -3-diethylaminoprop-1-enyl) -4-fluorobenzenesulfonyl- amino] -2,3-dihydro-1H- benzo [ d] pyrrolo [l, 2-a] imidazole-5-carboxylate

Figure pct00072

To a solution of methyl 6- (2-bromo-4-fluorobenzenesulfonylamino) -2,3-dihydro-1H- benzo [d] pyrrolo [1,2 yl) -a] imidazole-5-carboxylate (intermediate 54, 0.264 g) and N, N - diethyl- -Amine (intermediate 3, 0.453 g) was purged with nitrogen and then treated with tris- (dibenzylideneacetone) dipalladium (0) (0.046 g) and tri- tert -butylphosphonium tetrafluoroborate 0.029 g). The reaction mixture was heated at 95 &lt; 0 &gt; C for 2 hours under a nitrogen atmosphere. After cooling, dilute the mixture with ethyl acetate and, after washed with water, dried (Na 2 SO 4) and then, filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica eluting with DMAW-120 to give a pale brown gum which was purified by silica eluting with a gradient of 0-30% using a mixture of methanol and DCM To give methyl 6- [2- ((Z) -3-diethylaminoprop-1-enyl) -4-fluorobenzenesulfonylamino] -2,3-dihydro- Benzo [d] pyrrolo [l, 2-a] imidazole-5-carboxylate (0.166 g) as a colorless gum.

1 H NMR (CDCl 3) δ : 8.07 (1H, dd), 7.47 (1H, d), 7.37 (1H, d), 7.03 (1H, dt), 6.93 (2H, m), 6.06 (1H, m) (2H, m), 2.63 (4H, br, q), 0.97 (2H, t), 4.11 (2H, t), 4.00 , t).

Intermediate 54: Methyl 6- (2-Bromo-benzenesulfonylamino to the parent-4-fluorobenzyl) -2,3-dihydro -1H- benzo [d] pyrrolo [1,2-a] imidazol-5-yl Carboxylate

Figure pct00073

2-Bromo-4-fluorobenzenesulfonyl chloride (0.410 g) was added to a solution of methyl 6-amino-2,3-dihydro-lH- benzo [d] pyrrolo [ [1,2-a] imidazole-5-carboxylate (intermediate product 55, 0.290 g) and the resulting mixture was stirred at room temperature for 24 hours. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried (Na 2 SO 4) and then, filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica eluting with a gradient of 0-15% using a mixture of methanol and DCM to give a sandy solid which was triturated with ether and filtered to give methyl Dihydro-lH-benzo [d] pyrrolo [1,2-a] imidazole-5-carboxylate (0.268 g, ).

1 H NMR (CDCl 3) δ : 8.16 (1H, dd), 7.51 (1H, d), 7.33 (2H, m), 7.05 (1H, dt), 4.09 (2H, t), 4.08 (3H, s) , 3.13 (2 H, t), 2.71 (2 H, m).

Intermediate 55: Methyl 6-amino-2,3-dihydro-1H-benzo [d] pyrrolo [1,2- a] imidazole-

Figure pct00074

To a solution of methyl 6- (2,2-dimethylpropionylamino) -2,3-dihydro-1H benzo [d] pyrrolo [1,2- a] imidazole-5-carboxylate ( Intermediate 56, 0.61 g) and concentrated sulfuric acid (1.5 ml) was stirred and heated under reflux for 44 hours. After cooling, the solution was concentrated in vacuo and the residue was dissolved in water and ethyl acetate and then basified with 5M sodium hydroxide solution. After extracting the aqueous phase with ethyl acetate (x8), dried the combined extracts (Na 2 SO 4), and filtered. The filtrate was concentrated in vacuo and the residue was triturated with ether and filtered to give methyl 6-amino-2,3-dihydro-1H- benzo [d] pyrrolo [ Carboxylate (0.296 g) as an off-white solid.

1 H NMR (DMSO-d 6 ) δ: 7.37 (1H, d), 6.61 (1H, d), 6.39 (2H, br, s), 4.03 (2H, t), 3.81 (3H, s), 2.90 ( 2H, t), 2.59 (2H, m).

Intermediate 56: Methyl 6- (2,2-dimethylpropionylamino) -2,3-dihydro-1H benzo [d] pyrrolo [

Figure pct00075

To a solution of methyl 6- (2,2-dimethylpropionylamino) -2-nitro-3- (2-oxopyrrolidin-1-yl) -benzoate (intermediate 57, 0.89 g, ) And iron powder (1.37 g) was stirred and heated at 115 [deg.] C for 2.5 hours. After cooling, the mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate and 2M sodium hydroxide solution and then filtered through celite. The organic phase was dried (Na 2 SO 4 ) then filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica eluting with a gradient of 50-100% using a mixture of ethyl acetate and cyclohexane. The product was purified by chromatography on silica eluting with a gradient of 0-10% using methanol and ethyl acetate to give methyl 6- (2,2-dimethylpropionylamino) -2,3-dihydro- LH-benzo [d] pyrrolo [l, 2-a] imidazole-5-carboxylate (0.616 g) as an off-white solid.

LCMS (Method A) r / t 2.26 (M + H) 316

Intermediate 57: Methyl 6- (2,2-dimethylpropionylamino) -2-nitro-3- (2- oxopyrrolidin- 1 -yl) -benzoate

Figure pct00076

A solution of N, N'-dimethylethylenediamine (1.72 g) in toluene (15 ml) was added to a solution of methyl 3-bromo-6- (2,2- dimethylpropionylamino) -2-nitro- (0.489 g), copper (I) iodide (0.091 g) and potassium carbonate (1.32 g), and the mixture was stirred and purged with nitrogen 0.0 &gt; 110 C &lt; / RTI &gt; for 5 hours. After cooling, the mixture was diluted with water and ethyl acetate, then organic phase was dried (Na 2 SO 4), and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica eluting with a gradient of 10-80% using a mixture of ethyl acetate and cyclohexane to give methyl 6- (2,2-dimethylpropyl) (2-oxopyrrolidin-1-yl) -benzoate (0.310 g) as an off-white solid.

1 H NMR (CDCl 3) δ : 10.25 (1H, br, s), 8.79 (1H, d), 7.44 (1H, d), 3.89 (3H, s), 3.75 (2H, t), 2.50 (2H, t), 2.22 (2H, m), 1.33 (9H, s).

Intermediate 58: Methyl 3-bromo-6- (2,2-dimethylpropionylamino) -2-nitro-benzoate

Figure pct00077

Trimethylacetyl chloride (5.09 g) was added to a solution of methyl 6-amino-3-bromo-2-nitro-benzoate (Brock et al Tertrahedron , 1963 , 19 , 1911], 7.74 g) and allowed to stand at room temperature for 3 hours. The mixture was concentrated in vacuo and the residue was dissolved in DCM and 1 M hydrochloric acid and then filtered through a phase separator. The filtrate was concentrated in vacuo and the residue was triturated with pentane. The resulting solid was filtered to give methyl 3-bromo-6- (2,2-dimethylpropionyl-amino) -2-nitrobenzoate (9.17 g).

LCMS (Method A) r / t 4.23 (M-H) 357, 359

Biological Example:

Compounds are tested for their ability to inhibit recombinant human MetAP2 activity using the following assays.

After Sf9 cells expressing the human recombinant flag -MetAP2 within, affinity purification, and the EDTA treated to remove endogenous active site cations, and dialyzed against the MnCl 2, was prepared in manganese the enzyme used in the assay. This assay uses 100 mM NaCl at pH 7.5 in the presence of 0.75 mM methionine-alanine-serine (MAS) substrate and 50 [mu] g / ml amino acid oxidase using a dilution of purified MetAP2, Gt; 25 C &lt; / RTI &gt; for 30 minutes in 50 mM HEPES buffer. The cleavage of the substrate by MetAP2 and the oxidation of the free methionine by the amino acid oxidase are carried out in combination with horseradish peroxidase which detects H 2 O 2 released during the oxidation step and the Amplex red ) (10-acetyl-3, &lt; / RTI &gt; 7-dihydroxy phenoxazine). Fluorescence signals were detected using a multi-well fluorescence meter. The compound was diluted in DMSO before assaying the buffer so that the final DMSO concentration was 1% on assay.

IC 50 is defined as the concentration at which a given compound achieves 50% inhibition of the control. IC 50 values are calculated using the XLfit software package (version 2.0.5).

The compounds of the present invention demonstrated activity in the assays of this example as indicated in the table below, wherein A represents an IC 50 < 0.05 μM, B represents an IC 50 from 0.05 μM to 0.5 μM, C represents an IC 50 > 0.5 μM.

Figure pct00078

Nested by references

All publications and patents mentioned herein, including the items listed below, are incorporated herein by reference for all purposes, as if each publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application will control, including any definitions defined herein.

Equal

Although specific embodiments of the invention have been discussed, the foregoing description is intended to be illustrative, not limiting. Many modifications of the invention will be apparent to those skilled in the art in light of this disclosure. The full scope of the invention should be determined with reference to the specification, along with the full scope of equivalents, as well as the appended claims.

Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, etc. used in the specification and claims are to be understood as being modified in all instances by the term "about ". Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and the appended claims are approximations that may vary depending upon the properties sought to be obtained by the present invention.

The following are the claims:

Claims (37)

  1. A tricyclic compound represented by the following formula (I); And their pharmaceutically acceptable salts, stereoisomers, esters and precursors:
    (I)
    Figure pct00079

    Wherein,
    D is a 5- to 7-membered heterocyclic or heteroaromatic ring, one of the two atoms in common between ring B and ring D is nitrogen and the other is carbon;
    B is a 4 to 6 membered saturated or partially unsaturated heterocyclic heterocyclic ring; Ring B may be optionally substituted by one or more fluorine atoms on any one of the available carbon atoms;
    X is + -C (R D1 R D2) - *, + -C (R C1) = *, + -N = *, + -C (R D1 R D2) -C (R D5 R D6) - *, + -C (R C1) = C (R C2) - *, + -W 1 -C (R D5 R D6) - *, + -W 1 -C (O) - *, + -C (R D1 R D2) -C (R D3 R D4 ) -C (R D5 R D6) - *, + -W 1 -C (R D3 R D4) -C (R D5 R D6) - *, + -W 1 -C (O) -C (R D5 R D6) - *, + -C (R D1 R D2) -W 2 -C (R D5 R D6) - *, + -C (R D1 R D2) -W 2 - C (O) - * doedoe selected from the group consisting of; + And * represent attachment points of X as shown in formula I;
    Y is selected from the group consisting of * -CH 2 - # , * -CH 2 -CH 2 - # , * -CH 2 -CH 2 -CH 2 - # , * -CH 2 -O-CH 2 - # ; * And # represent attachment points of Y as shown in formula (I);
    W 1 is selected from the group consisting of O or N (R N1 );
    W 2 is selected from the group consisting of O or N (R N2 );
    A is phenyl, 5 to 6 membered heteroaryl having 1, 2 or 3 heteroatoms each selected from S, N or O, and 4 to 7 membered heteroaryl having 1, 2 or 3 heteroatoms each selected from N or O, A heterocycle;
    R A1 is independently selected from the group consisting of hydrogen, hydroxyl, cyano, halogen, C 1-4 alkyl or C 1-3 alkoxy for each occurrence; C 1-4 alkyl or C 1-3 alkoxy may be optionally substituted with one or more fluorines;
    n is 1 or 2;
    R A2 is selected from the group consisting of hydrogen, R i R j N-, heterocyclyl, heterocyclyloxy, heterocyclyl- (NR a ) -; Said heterocyclyl may be optionally substituted with one or more substituents selected from R g ; If said heterocyclyl comprises an -NH moiety, said nitrogen may be optionally substituted with one or more groups R h ; or
    R A2 is selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 alkenyloxy, C 3-6 alkynyl oxy, C 3-6 cycloalkoxy, C 1-6 alkyl, -S (O) w - (w is 0, 1 or 2), C 1-6 alkyl -N (R a) -, C 1-6 alkyl -N (R a) - carbonyl -, C 1-6 alkylcarbonyl -N (R a) -, C 1-6 alkyl -N (R a) - carbonyl -N (R a) -, C 1 -6 alkyl, -N (R a) -SO 2 - , C 1-6 alkyl, -SO 2 -N (R a) - , C 1-6 alkoxycarbonyl -N (R a) -, C 1-6 alkyl carbonyl -N (R a) -C 1-6 alkyl -, C 1-6 alkyl -N (R a) - a-carbonyl group -C 1-6 alkyl -, C 1-6 alkoxy C 1-6 alkyl &Lt; / RTI &gt; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 alkenyloxy, C 3-6 alkynyloxy, C 3-6 cycloalkoxy, C 1-6 alkyl, -S (O) w -, C 1-6 alkyl -N (R a) -, C 1-6 alkyl -N (R a) - carbonyl -, C 1 -6 alkylcarbonyl -N (R a) -, C 1-6 alkyl -N (R a) - carbonyl -N (R a) -, C 1-6 alkyl -N (R a) -SO 2 - , C 1-6 alkyl, -SO 2 -N (R a) - , C 1-6 alkoxycarbonyl -N (R a) -, C 1-6 alkylcarbonyl -N (R a) C 1-6 alkyl, -, C 1-6 alkyl-N (R a ) -carbonyl-C 1-6 alkyl-, C 1-6 alkoxy-C 1-6 alkyl is R P , phenyl, phenoxy, , Heteroaryl- (NR a ) -, heterocyclyl, heterocyclyloxy or heterocyclyl-N (R a ) -; Wherein said heteroaryl or phenyl may be optionally substituted with one or more substituents selected from R f ; Said heterocyclyl may be optionally substituted with one or more substituents selected from R g ; If the heterocyclyl comprises an -NH moiety, the nitrogen may be optionally substituted with one or more groups R h ;
    R D1 and R D2 are each independently selected from the group consisting of hydrogen, fluorine, hydroxyl, C 1-2 alkyl or C 1-2 alkoxy; The C 1-2 alkyl and C 1-2 alkoxy may be optionally substituted with one or more fluorine atoms, or a group selected from cyano or hydroxyl;
    R D3 and R D4 are each independently selected from the group consisting of hydrogen, fluorine, hydroxyl, cyano, C 1-3 alkyl or C 1-3 alkoxy; The C 1-3 alkyl and C 1-3 alkoxy may be optionally substituted with one or more fluorine atoms, or a group selected from cyano, hydroxyl or N (R a R b );
    R D5 and R D6 are each independently selected from the group consisting of hydrogen, fluorine, hydroxyl, cyano, C 1-2 alkyl or C 1-2 alkoxy; The C 1-2 alkyl and C 1-2 alkoxy may be optionally substituted with one or more fluorine atoms, or a group selected from cyano, hydroxyl or N (R a R b )
    R C1 is selected from the group consisting of hydrogen, halogen, C 1-2 alkyl or C 1-2 alkoxy; Said C 1-2 alkyl or C 1-2 alkoxy optionally substituted with one or more fluorine atoms;
    R C2 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C 1-2 alkyl or C 1-2 alkoxy; Wherein the C 1-2 alkyl and C 1-2 alkoxy may be optionally substituted with one or more fluorine atoms, or a group selected from cyano, hydroxyl or N (R a R b );
    R N1 is selected from the group consisting of hydrogen or C 1-2 alkyl;
    R N2 is selected from the group consisting of hydrogen, C 1-3 alkyl or C 1-2 alkylcarbonyl; The C 1-3 alkyl and C 1-2 alkylcarbonyl may be optionally substituted with one or more fluorine atoms, or a group selected from cyano, hydroxyl or N (R a R b );
    R a and R b are independently selected from the group consisting of hydrogen and C 1-3 alkyl for each occurrence; C 1-3 alkyl may be optionally substituted with one or more substituents selected from fluorine, cyano, oxo, and hydroxyl;
    Or R & lt ; a & gt ; and R &lt; b & gt ; may form, together with the nitrogen to which they are attached, a 4 to 6 membered heterocyclic ring which may bear an additional heteroatom selected from O, S or N; The 4 to 6 membered heterocyclic ring may be optionally substituted on carbon by one or more substituents selected from the group consisting of fluorine, cyano, oxo, or hydroxyl;
    R f is, for each occurrence, R P, hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1 -6 alkoxy, C 1-6 alkyl, -S (O) w - (w is 0, 1 or 2), C 1-6 alkylcarbonyl -N (R a) -; Ci- 6 alkoxycarbonyl-N (R &lt; a &gt;)-; C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkyl, -S (O) w- , C 1-6 alkylcarbonyl-N (R a ) -, C 1-6 alkoxycarbonyl-N (R a ) - may be optionally substituted with one or more substituents selected from R p ;
    R g is, for each case R P, hydrogen, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1- 6 alkyl, -S (O) w - (w is 0, 1 or 2), C 1-6 alkylcarbonyl -N (R a) -, C 1-6 alkoxycarbonyl -N (R a) - a &Lt; / RTI &gt; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkyl, -S (O) w -, C 1-6 Alkylcarbonyl-N (R a ) -, C 1-6 alkoxycarbonyl-N (R a ) - may be optionally substituted with one or more substituents selected from R p ;
    R h is, for each case hydrogen, C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkyl, -S (O) 2 -, C 1-6 alkoxycarbonyl -, R i R j N- carbonyl -, R i R j N- SO 2 - doedoe independently selected from the group consisting of; C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkyl, -S (O) 2 -, C 1-6 alkyl-carbonyl-R is Lt ; RTI ID = 0.0 &gt; P &lt; / RTI &gt;
    R i and R j are independently selected from the group consisting of hydrogen, C 1-4 alkyl and C 3-6 cycloalkyl for each occurrence; C 1-4 alkyl and C 3-6 cycloalkyl are optionally substituted with one or more substituents selected from fluorine, hydroxyl, cyano, R a R b N-, R a R b N-carbonyl-, C 1-3 alkoxy Optionally substituted;
    Or R i and R j, together with the nitrogen to which they are attached, fluorine, hydroxyl, oxo, cyano, C 1-6 alkyl, C 1-6 alkoxy, R a R b N-, R a R b N- SO 2 -, R a R b N- carbonyl-4, which may have an additional heteroatom selected from optionally, O, S or N substituted in the on-carbon by one or more substituents selected from the group consisting of to 7 To form a heterocyclic ring; Wherein said C 1-6 alkyl or C 1-6 alkoxy may be optionally substituted with fluorine, hydroxyl or cyano; Which may be optionally substituted on the nitrogen by one or more substituents selected from the group consisting of C 1-6 alkyl, R a R b N-carbonyl-; Said C 1-6 alkyl may be optionally substituted with fluorine, hydroxyl, or cyano;
    R P is, for each occurrence, halogen, hydroxyl, cyano, C 1-6 alkoxy, R i R j N-, R i R j N- carbonyl -, R i R j N- SO 2 -, R i R j N-carbonyl-N (R a ) -.
  2. The method of claim 1 wherein, X is + -C (R D1 R D2) - *, + -C (R C1) = *, + -N = *, + -C (R D1 R D2) -C (R D5 R D6) - *, + -OC (R D5 R D6) - *, + -N (R N1) -C (R D5 R D6) - * and + -OC (R D3 R D4) -C (R D5 R D6) - * doedoe selected from the group consisting of; + & Amp ; * represent attachment points of X as indicated in formula (I).
  3. 3. A method according to claim 1 or 2, wherein, X is + -CH 2 - *, + -CH = *, + -N = *, + -OCH 2 - * + NHCH 2 - * and + CH 2 CH 2 - * &Lt; / RTI &gt; + & Amp ; * represent attachment points of X as indicated in formula (I).
  4. 4. The tricyclic compound according to any one of claims 1 to 3, wherein R D1 , R D2 , R C1 and R N1 are independently selected from the group consisting of hydrogen and methyl for each occurrence.
  5. 4. The tricyclic compound according to any one of claims 1 to 3, wherein R D1 , R D2 , R C1 and R N1 are hydrogen.
  6. 6. Compounds according to any one of claims 1 to 5, wherein R D3 , R D4 , R D5 and R D6 are independently selected from the group consisting of hydrogen, fluorine, cyano and C 1-2 alkyl for each occurrence Lt; / RTI &gt;
  7. 6. The tricyclic compound according to any one of claims 1 to 5, wherein R D3 , R D4 , R D5 and R D6 are hydrogen.
  8. 8. A tricyclic compound according to any one of claims 1 to 7, wherein R C2 is selected from the group consisting of hydrogen, halogen, cyano and C 1-2 alkyl.
  9. 8. The tricyclic compound according to any one of claims 1 to 7, wherein R C2 is hydrogen.
  10. 10. A tricyclic compound according to any one of claims 1 to 9, wherein R N2 is selected from the group consisting of hydrogen and C 1-2 alkyl.
  11. 10. The tricyclic compound according to any one of claims 1 to 9, wherein R N2 is hydrogen.
  12. 12. The tricyclic compound according to any one of claims 1 to 11, wherein D is selected from the group consisting of:
    (I)
    Figure pct00080
    ;
    Figure pct00081

    Wherein * and # represent attachment points for Y, and + represents one of attachment points for a phenyl ring as shown in formula I.
  13. 13. The compound according to any one of claims 1 to 12,
    Figure pct00082

    &Lt; / RTI &gt;
  14. The method according to any one of claims 13, wherein, Y represents * -CH 2 - #, * -CH 2 -CH 2 - #, * -CH 2 -O-CH 2 - is selected from the group consisting of # Lt; / RTI &gt;
  15. Any one of claims 1 to 14. A method according to any one of claims, wherein, Y represents * -CH 2 -CH 2 - # would the tricyclic compound.
  16. 16. A tricyclic compound according to any one of claims 1 to 15, wherein B is selected from the group consisting of:
    (I)
    Figure pct00083
    ;
    Figure pct00084

    Wherein * and # denote secondary points for Y as shown in formula (I).
  17. 17. The compound according to any one of claims 1 to 16, wherein B is &lt; RTI ID = 0.0 &gt;
    Figure pct00085

    &Lt; / RTI &gt;
  18. 2. The compound according to claim 1,
    Figure pct00086

    Figure pct00087

    &Lt; / RTI &gt;
  19. 19. The tricyclic compound of claim 18, wherein A is phenyl.
  20. A tricyclic compound represented by the following formula (II); And their pharmaceutically acceptable salts, stereoisomers, esters and precursors:
    (II);
    Figure pct00088

    Wherein,
    D is a 5- to 7-membered heterocyclic or heteroaromatic ring, one of the two atoms in common between ring B and ring D is nitrogen and the other is carbon;
    B is a 4 to 6 membered saturated or partially unsaturated heterocyclic heterocyclic ring; The B ring may be optionally substituted with one or more fluorine atoms on any one of the available carbon atoms;
    X is + -C (R D1 R D2) - *, + -C (R C1) = *, + -N = *, + -C (R D1 R D2) -C (R D5 R D6) - *, + -C (R C1) = C (R C2) - *, + -W 1 -C (R D5 R D6) - *, + -W 1 -C (O) - *, + -C (R D1 R D2) -C (R D3 R D4 ) -C (R D5 R D6) - *, + -W 1 -C (R D3 R D4) -C (R D5 R D6) - *, + -W 1 -C (O) -C (R D5 R D6) - *, + -C (R D1 R D2) -W 2 -C (R D5 R D6) - *, + -C (R D1 R D2) -W 2 - C (O) - * doedoe selected from the group consisting of; + And * represent attachment points of X as shown in formula I;
    Y is selected from the group consisting of * -CH 2 - # , * -CH 2 -CH 2 - # , * -CH 2 -CH 2 -CH 2 - # , * -CH 2 -O-CH 2 - # ; * And # represent attachment points of Y as shown in formula (I);
    W 1 is selected from the group consisting of O or N (R N1 );
    W 2 is selected from the group consisting of O or N (R N2 );
    R A1 is independently selected from the group consisting of hydrogen, hydroxyl, cyano, halogen, C 1-4 alkyl or C 1-3 alkoxy for each occurrence; C 1-4 alkyl or C 1-3 alkoxy may be optionally substituted with one or more fluorines;
    n is 1 or 2;
    R A2 is independently selected from the group consisting of hydrogen, R i R j N-, heterocyclyl, heterocyclyloxy, heterocyclyl- (NR a ) -; The heterocyclyl may be optionally substituted with one or more substituents selected from R g ; If said heterocyclyl comprises an -NH moiety, said nitrogen may be optionally substituted with one or more groups R h ; or
    R A2 is selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 alkenyloxy, C 3-6 alkynyl oxy, C 3-6 cycloalkoxy, C 1-6 alkyl, -S (O) w - (w is 0, 1 or 2), C 1-6 alkyl -N (R a) -, C 1-6 alkyl -N (R a) - carbonyl -, C 1-6 alkylcarbonyl -N (R a) -, C 1-6 alkyl -N (R a) - carbonyl -N (R a) -, C 1 -6 alkyl, -N (R a) -SO 2 - , C 1-6 alkyl, -SO 2 -N (R a) - , C 1-6 alkoxycarbonyl -N (R a) -, C 1-6 alkyl carbonyl -N (R a) -C 1-6 alkyl -, C 1-6 alkyl -N (R a) - a-carbonyl group -C 1-6 alkyl -, C 1-6 alkoxy C 1-6 alkyl &Lt; / RTI &gt; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 alkenyloxy, C 3-6 alkynyloxy, C 3-6 cycloalkoxy, C 1-6 alkyl, -S (O) w -, C 1-6 alkyl -N (R a) -, C 1-6 alkyl -N (R a) - carbonyl -, C 1 -6 alkylcarbonyl -N (R a) -, C 1-6 alkyl -N (R a) - carbonyl -N (R a) -, C 1-6 alkyl -N (R a) -SO 2 - , C 1-6 alkyl, -SO 2 -N (R a) - , C 1-6 alkoxycarbonyl -N (R a) -, C 1-6 alkylcarbonyl -N (R a) C 1-6 alkyl, -, C 1-6 alkyl-N (R a ) -carbonyl-C 1-6 alkyl-, C 1-6 alkoxy-C 1-6 alkyl is R P , phenyl, phenoxy, , Heteroaryl- (NR a ) -, heterocyclyl, heterocyclyloxy or heterocyclyl-N (R a ) -; Wherein said heteroaryl or phenyl may be optionally substituted with one or more substituents selected from R f ; Said heterocyclyl may be optionally substituted with one or more substituents selected from R g ; If the heterocyclyl comprises an -NH moiety, the nitrogen may be optionally substituted with one or more groups R h ;
    R D1 and R D2 are each independently selected from the group consisting of hydrogen, fluorine, hydroxyl, C 1-2 alkyl or C 1-2 alkoxy; The C 1-2 alkyl and C 1-2 alkoxy may be optionally substituted with one or more fluorine atoms, or a group selected from cyano or hydroxyl;
    R D3 and R D4 are each independently selected from the group consisting of hydrogen, fluorine, hydroxyl, cyano, C 1-3 alkyl or C 1-3 alkoxy; The C 1-3 alkyl and C 1-3 alkoxy may be optionally substituted with one or more fluorine atoms, or a group selected from cyano, hydroxyl or N (R a R b );
    R D5 and R D6 are each independently selected from the group consisting of hydrogen, fluorine, hydroxyl, cyano, C 1-2 alkyl or C 1-2 alkoxy; Wherein the C 1-2 alkyl and C 1-2 alkoxy may be optionally substituted with one or more fluorine atoms, or a group selected from cyano, hydroxyl or N (R a R b );
    R C1 is selected from the group consisting of hydrogen, halogen, C 1-2 alkyl or C 1-2 alkoxy; Said C 1-2 alkyl or C 1-2 alkoxy optionally substituted with one or more fluorine atoms;
    R C2 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C 1-2 alkyl or C 1-2 alkoxy; Wherein the C 1-2 alkyl and C 1-2 alkoxy may be optionally substituted with one or more fluorine atoms, or a group selected from cyano, hydroxyl or N (R a R b );
    R N1 is selected from the group consisting of hydrogen or C 1-2 alkyl;
    R N2 is selected from the group consisting of hydrogen, C 1-3 alkyl or C 1-2 alkylcarbonyl; The C 1-3 alkyl and C 1-2 alkylcarbonyl may be optionally substituted with one or more fluorine atoms, or a group selected from cyano, hydroxyl or N (R a R b );
    R a and R b are independently selected from the group consisting of hydrogen and C 1-3 alkyl for each occurrence; C 1-3 alkyl may be optionally substituted with one or more substituents selected from fluorine, cyano, oxo, and hydroxyl;
    Or R & lt ; a & gt ; and R &lt; b & gt ; may form, together with the nitrogen to which they are attached, a 4 to 6 membered heterocyclic ring which may bear an additional heteroatom selected from O, S or N; The 4 to 6 membered heterocyclic ring may be optionally substituted on carbon by one or more substituents selected from the group consisting of fluorine, cyano, oxo, or hydroxyl;
    R f is, for each occurrence, R P, hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1 -6 alkoxy, C 1-6 alkyl, -S (O) w - (w is 0, 1 or 2), C 1-6 alkylcarbonyl -N (R a) -; Ci- 6 alkoxycarbonyl-N (R &lt; a &gt;)-; C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkyl, -S (O) w- , C 1-6 alkylcarbonyl-N (R a ) -, C 1-6 alkoxycarbonyl-N (R a ) - may be optionally substituted with one or more substituents selected from R p ;
    R g is, for each case R P, hydrogen, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1- 6 alkyl, -S (O) w - (w is 0, 1 or 2), C 1-6 alkylcarbonyl -N (R a) -, C 1-6 alkoxycarbonyl -N (R a) - a &Lt; / RTI &gt; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkyl, -S (O) w -, C 1-6 Alkylcarbonyl-N (R a ) -, C 1-6 alkoxycarbonyl-N (R a ) - may be optionally substituted with one or more substituents selected from R p ;
    R h is, for each case hydrogen, C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkyl, -S (O) 2 -, C 1-6 alkoxycarbonyl -, R i R j N- carbonyl -, R i R j N- SO 2 - doedoe independently selected from the group consisting of; C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkyl, -S (O) 2 -, C 1-6 alkyl-carbonyl-R is Lt ; RTI ID = 0.0 &gt; P &lt; / RTI &gt;
    R i and R j are independently selected from the group consisting of hydrogen, C 1-4 alkyl and C 3-6 cycloalkyl for each occurrence; C 1-4 alkyl and C 3-6 cycloalkyl are optionally substituted with one or more substituents selected from fluorine, hydroxyl, cyano, R a R b N-, R a R b N-carbonyl-, C 1-3 alkoxy Optionally substituted;
    Or R i and R j, together with the nitrogen to which they are attached, fluorine, hydroxyl, oxo, cyano, C 1-6 alkyl, C 1-6 alkoxy, R a R b N-, R a R b N- SO 2 -, R a R b N- carbonyl-4, which may have an additional heteroatom selected from optionally, O, S or N substituted in the on-carbon by one or more substituents selected from the group consisting of to 7 To form a heterocyclic ring; Wherein said C 1-6 alkyl or C 1-6 alkoxy may be optionally substituted with fluorine, hydroxyl or cyano; C 1-6 alkyl, R a R b N-carbonyl-, and the like; Said C 1-6 alkyl may be optionally substituted with fluorine, hydroxyl, or cyano;
    R P is, for each occurrence, halogen, hydroxyl, cyano, C 1-6 alkoxy, R i R j N-, R i R j N- carbonyl -, R i R j N- SO 2 -, R i R j N-carbonyl-N (R a ) -.
  21. 21. The compound of claim 20, wherein R A1 is selected from the group consisting of hydrogen, halogen, C 1-2 alkyl, C 1-2 alkoxy; C 1-2 alkyl is optionally substituted with one or more fluorine.
  22. 21. The tricyclic compound of claim 20, wherein R A1 is selected from hydrogen or fluorine.
  23. 23. Compounds according to any one of claims 20-22, wherein R A2 is hydrogen, R 1 R j N, heterocyclyl, C 1-6 alkyl, C 3-6 alkenyl, C 3-6 cycloalkyl, C doedoe selected from the group consisting of 1-6 alkoxy; The heterocyclyl can be optionally substituted with one or more groups R g and, if the heterocyclyl contains an -NH moiety, the nitrogen can be optionally substituted with one or more groups R h ; Wherein said C 1-6 alkyl, C 3-6 alkenyl, C 3-6 cycloalkyl and C 1-6 alkoxy can be optionally substituted with one or more groups R P.
  24. 23. Compounds according to any one of claims 20-22, wherein R A2 is 3- (N, N-diethylamino) propyl, 3- (pyrrolidin- (Z) -3- (pyrrolidin-1-yl) propyl-1-enyl, ) Prop-1-enyl. &Lt; / RTI &gt;
  25. (R) -7- [2 - ((Z) -3-diethylaminoprop-1-enyl) -4-fluorobenzenesulfonyl-amino] -2,3,3a, 4-tetrahydro- -Benzo [b] pyrrolo [1,2-d] [l, 4] oxazine-6-carboxylic acid; (S) -7- [2 - ((Z) -3-diethylaminoprop-1-enyl) -4-fluorobenzenesulfonyl-amino] -2,3,3a, 4-tetrahydro- -Benzo [b] pyrrolo [1,2-d] [l, 4] oxazine-6-carboxylic acid; Dihydro-lH-pyrrolo [1,2-a] pyrimidin-7-ylmethyl) ] Indole-8-carboxylic acid; 7-Benzenesulfonylamino-2,3-dihydro-lH-pyrrolo [l, 2-a] indole-8-carboxylic acid; 7- [2 - ((Z) -3-diethylaminoprop-1-enyl) -4-fluorobenzenesulfonylamino] -2,3,9,9a-tetrahydro-lH- pyrrolo [ , 2-a] indole-8-carboxylic acid; (R) -7- [2 - ((Z) -3- diethylaminoprop-1-enyl) -4-fluorobenzenesulfonylamino] -2,3,9,9a-tetrahydro- Pyrrolo [l, 2-a] indole-8-carboxylic acid; (S) -7- [2- ((Z) -3-diethylaminoprop-1-enyl) -4-fluorobenzenesulfonylamino] -2,3,9,9a-tetrahydro- Pyrrolo [l, 2-a] indole-8-carboxylic acid; 7- [2 - ((Z) -3-diethylaminoprop-1-enyl) -4-fluorobenzenesulfonyl-amino] -1,2,3,3a, 4,5-hexahydropyrrolo [L, 2-a] quinoline-6-carboxylic acid; (R) -6- [2 - ((Z) -3-diethylaminoprop-1-enyl) -4-fluorobenzene-esulphonylamino] -1,2,2a, 3- tetrahydro- 4-oxa-8b-azacyclobuta [a] naphthalene-5-carboxylic acid; Dihydro-lH-benzo [d] pyrrolo [2,3-d] pyrimidin-4- 1,2-a] imidazole-5-carboxylic acid; And their pharmaceutically acceptable salts, stereoisomers, esters and precursors.
  26. 26. A pharmaceutically acceptable composition comprising a compound of any one of claims 1 to 25 and a pharmaceutically acceptable excipient.
  27. 26. A method of treating and / or modulating obesity comprising administering to a patient in need thereof an effective amount of a compound of any one of claims 1 to 25.
  28. 26. A method of inducing weight loss in a patient in need of weight reduction comprising administering to said patient an effective amount of a compound of any one of claims 1 to 25.
  29. 29. The method of claim 27 or 28, wherein said patient is a human.
  30. 29. The method of claim 27 or 28, wherein the patient is a cat or a person.
  31. 30. A method according to any one of claims 27 to 29, wherein the patient has a body mass index of at least about 30 kg / m 2 prior to administration.
  32. 32. The method according to any one of claims 27 to 31, wherein said compound is administered orally.
  33. 27. The pharmaceutical composition of claim 26, wherein the composition is formulated as a unit dose.
  34. 27. The pharmaceutical composition of claim 26, wherein said composition is formulated for oral administration.
  35. 27. The pharmaceutical composition of claim 26, wherein the composition is formulated for intravenous or subcutaneous administration.
  36. 29. The method of claim 27 or 28 wherein said compound is administered in an amount sufficient to establish inhibition of intracellular MetAP2 effective in increasing thioredoxin production in said subject and inducing multicenter stimulation of the anti- &Lt; / RTI &gt;
  37. 37. The method of claim 36, comprising administering the compound in an amount insufficient to reduce angiogenesis in the patient.
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